FLAGELLIN-BASED AGENTS AND USES INCLUDING EFFECTIVE VACCINATION

Abstract

The present invention relates to, in part, compositions comprising improved flagellin derived constructs and methods of using for vaccination, including adjuvants comprising flagellin-based agents.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. Patent Application No. 15/500,133, filed Jan. 30, 2017, which is a national stage entry of International Patent Application No. PCT/US2015/042887, filed Jul. 30, 2015, which claims the benefit of U.S. Provisional Patent Application Nos. 62/031,116, filed Jul. 30, 2014; 62/110,744, filed Feb. 2, 2015; and 62/117,366, filed Feb. 17, 2015 the entire contents of which are herein incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to, inter a/ia, new compositions and methods for vaccination, including adjuvants comprising flagellin-based agents.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

[0003] The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: CLE019PC SequenceListing.txt; date recorded: Jul. 24, 2015; file size: 261 KB).

BACKGROUND

[0004] Vaccines are one of the most effective preventative health tools available against infectious diseases, cancers, and allergies. Vaccination aims to generate a strong immune response to the administrated antigen and provide long-term protection against a disorder. Often, however, an antigen alone is insufficient to stimulate protective immunity.

[0005] Vaccine adjuvants are compounds that enhance the specific immune responses against antigens in vaccines. Currently, several hundred natural and synthetic compounds are known to have adjuvant activity but only alum salts and AS04 are licensed for use in humans in the United States. This limited list of adjuvants is insufficient for meeting the functional needs of effective vaccination. For example, although alum is able to induce a good T.sub.H2 response, it has little capacity to stimulate cellular (T.sub.H1) immune responses which are so important for protection against many pathogens.

[0006] Accordingly, there remains a need for improved vaccines and/or adjuvants that can effectively stimulate a subject's immune response.

SUMMARY OF THE INVENTION

[0007] Accordingly, in some aspects, the present invention provides for improved vaccines and/or adjuvants.

[0008] In some aspects, the present invention provides a vaccine composition, comprising an adjuvant comprising a flagellin-based agent, such as, for example, CBLB502 (a/k/a entolimod) as well as any of the flagellin-based agents or derivatives described herein (e.g. Table 1), and an aluminum gel or salt and an antigen and, optionally, an additional adjuvant. In some aspects, the present invention provides an adjuvant composition, comprising an adjuvant comprising a flagellin-based agent, including CBLB502 as well as any of the flagellin-based agents or derivatives described herein (e.g. Table 1), and an aluminum gel or salt. In various embodiments, the vaccine described herein causes an improvement in adjuvant properties relative to a vaccine comprising the antigen and the aluminum gel or salt alone. In various embodiments, the vaccine and/or adjuvant described herein causes a broader, more diverse, more robust and longer lasting immunostimulatory effect than the vaccine comprising the antigen and the aluminum gel or salt alone and/or the adjuvant comprising the aluminum gel or salt alone. In various embodiments, the vaccine and/or adjuvant described herein causes immunostimulation of one or more of T.sub.H1 and T.sub.H2-mediated immune response (e.g. both of T.sub.H1 and T.sub.H2-mediated immune response) and/or the vaccine and/or adjuvant described herein causes immunostimulation of T.sub.H1-mediated immune response at levels greater than a vaccine comprising the antigen and the aluminum gel or salt alone and/or the adjuvant comprising the aluminum gel or salt alone.

[0009] In some embodiments, the flagellin-based agent may be a flagellin molecule or flagellin-based agent, or variants thereof that has TLR5 agonist activity. The flagellin-based agent may comprise one or more of the sequences of Table 1 (SEQ ID Nos.: 1-252), or variants thereof that have TLR5 agonist activity and can include a variant of Salmonella dublin wild type flagellin (SEQ ID No: 1), CBLB502 (SEQ ID NO: 2) or variants thereof (including closely-related variants such as S33ML (SEQ ID NO: 35), CBLB502-485CT (CBLB533, SEQ ID NO: 71), and CBLB502-S33MX (SEQ ID NO: 150)) and more distantly related variants such as flagellin derivatives from a thermophilic microorganism or flagellin derivatives from a microorganism well-tolerated by human (e.g. SEQ ID NOs: 243-252). In some embodiments, the aluminum gel or salt is selected from aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate, and ALHYDROGEL.

[0010] In various embodiments, the present vaccine composition is part of the following vaccines (e.g. the antigens of these vaccines may be used as the antigen of the present vaccines): DTP (diphtheria-tetanus-pertussis vaccine), DTaP (diphtheria-tetanus-acellular pertussis vaccine), Hib (Haemophilus influenzae type b) conjugate vaccines, Pneumococcal conjugate vaccine, Hepatitis A vaccines, Poliomyelitis vaccines, Yellow fever vaccines, Hepatitis B vaccines, combination DTaP, Tdap, Hib, Human Papillomavirus (HPV) vaccine, Anthrax vaccine, and Rabies vaccine.

[0011] In various embodiments, the vaccine described herein is formed, in part, by mixing the flagellin-based agent and aluminum gel or salt to form a stable complex, the ratio (w/w) of flagellin-based agent to aluminum gel or salt being about 1:500 or less (e.g. about 1:500, or about 1:600, or about 1:700, or about 1:800, or about 1:900, or about 1:1000, or about 1:2000, or about 1:5000). In some embodiments, the flagellin-based agent and aluminum gel or salt are mixed in a ratio that is substantially below a loading capacity of the aluminum gel or salt. In some embodiments, the flagellin-based agent and antigen are adsorbed to the aluminum gel or salt.

[0012] In another aspect, the present invention provides a method of vaccinating a subject against a disorder, comprising administering an effective amount of a vaccine comprising an adjuvant comprising a flagellin-based agent and an aluminum gel or salt and an antigen associated with the disorder. In another aspect, the present invention provides a method of immunostimulating a subject in advance of or concurrent with vaccination, comprising administering an effective amount of an adjuvant comprising a flagellin-based agent and an aluminum gel or salt, wherein both T.sub.H1 and T.sub.H2-mediated immune responses are immunostimulated. In various embodiments the disorder is selected from infectious diseases, cancer, allergy, and autoimmune diseases (by way of example, diphtheria, tetanus, pertussis, influenza, pneumonia, hepatitis A, hepatitis B, polio, yellow fever, Human Papillomavirus (HPV) infection, various cancers, anthrax, rabies, Japanese Encephalitis, meningitis, measles, mumps, rubella, gastroenteritis, smallpox, typhoid fever, varicella (chickenpox), rotavirus, and shingles).

[0013] The details of the invention are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

BRIEF DESCRIPTION OF THE FIGURES

[0014] FIGS. 1A and 1B show the 13 conserved amino acids of flagellin that may be important for TLR5 activity. FIGS. 1A and 1B show a comparison of amino acid sequences of the conserved amino (FIG. 1A) and carboxy (FIG. 1B) terminus from 21 species of bacteria. The 13 conserved amino acids important for TLR5 activity are indicated by the letter "C" at the bottom of each column. The amino add sequences are identified by their accession numbers from TrEMBL (first letter=Q) or Swiss-Prot (first letter=P). With respect to FIG. 1A, SEQ ID Nos: 253-273 correspond to the sequences listed on the figure from top to bottom, respectively. With respect to FIG. 1B, SEQ ID Nos: 274-294 correspond to the sequences listed on the figure from top to bottom, respectively.

[0015] FIG. 2 shows ELISA data for the average response of five mouse treatment groups at the time point of 1 week post-boost. Panel A is total IgG, Panel B is IgG1, Panel C is IgG2a, Panel D is IgG2b and Panel E is IgG3. Groups 1-5 are defined in TABLE B (Example 2): Group 1 is also called "Untreated;" Group 2 is also called "OVA," Groups 3 is also called "OVA+Alum," Group 4 is also called "SA 1 .mu.g," and Group 5 is also called "SA 10 .mu.g."

[0016] FIG. 3 shows ELISA data for the average response of five mouse treatment groups at the time point of 2 weeks post-boost. Panel A is total IgG, Panel B is IgG1, Panel C is IgG2a, Panel D is IgG2b and Panel E is IgG3. Groups 1-5 are defined in TABLE B (Example 2): Group 1 is also called "Untreated;" Group 2 is also called "OVA," Groups 3 is also called "OVA+Alum," Group 4 is also called "SA 1 .mu.g," and Group 5 is also called "SA 10 .mu.g."

[0017] FIG. 4 shows ELISA data for the average response of five mouse treatment groups at the time point of 4 weeks post-boost. Panel A is total IgG, Panel B is IgG1, Panel C is IgG2a, Panel D is IgG2b and Panel E is IgG3. Groups 1-5 are defined in TABLE B (Example 2): Group 1 is also called "Untreated;" Group 2 is also called "OVA," Groups 3 is also called "OVA+Alum," Group 4 is also called "SA 1 .mu.g," and Group 5 is also called "SA 10 .mu.g."

[0018] FIG. 5 shows a determination of CBLB502/ALHYDROGEL activity using a cell-based NF-KB activation assay. CBLB502/ALHYDROGEL formulation (5 .mu.g/100 .mu.l) and ALHYDROGEL control were serially diluted in assay media 2000- to 13122000-fold (2.6-0.0004 .mu.g/ml aluminium) and incubated with 293-hTLR5-LacZ cells for 20 hr. Activity of .beta.-galactosidase was measured after addition of cell lysis buffer and ONPG substrate and expressed as optical density at 414 nm (OD414).

[0019] FIG. 6 shows NF-.kappa.B-inducing activity of CBLB502/ALHYDROGEL formulated with different CBLB502 doses. 293-hTLR5-LacZ cells were incubated with CBLB502/ALHYDROGEL suspensions prepared at CBLB502 doses ranging from 2.5 to 0.00015 .mu.g/100 .mu.l and diluted 200-fold with media. Activity of .beta.-galactosidase reporter enzyme was measured after 20 hr incubation.

[0020] FIG. 7 shows dose-response titration curves CBLB502/ALHYDROGEL generated with 293-hTLR5-LacZ reporter cells. CBLB502 was adsorbed to ALHYDROGEL at indicated doses (20 .mu.g/100 .mu.l: top panel, 0.31 .mu.g/100 .mu.l: middle panel and 0.078 .mu.g/100 .mu.l: bottom panel), serially diluted with media and assayed together with soluble CBLB502 standards.

[0021] FIG. 8 shows the activity of CBLB502/ALHYDROGEL (1 .mu.g/100 .mu.l dose) stored at 4.degree. C. for 2 and 6 days. NF-.kappa.B-inducing activity was measured using 293-hTLR5-LacZ reporter cell assay.

[0022] FIG. 9 shows pharmacokinetics of CBLB502 in mouse serum after subcutaneous injection of a 1 .mu.g dose of CBLB502 adsorbed to ALHYDROGEL 2%. The graph shows per-group mean serum CBLB502 concentrations and SEM (standard error of the mean) for each time point.

[0023] FIG. 10 shows induction of KC, G-CSF and IL-6 following s.c. administration of a 1 .mu.g dose of CBLB502 adsorbed to ALHYDROGEL 2%. Serum concentrations of the cytokines were determined using R&D Systems DuoSet kits DY453 (KC, top panel), DY414 (G-CSF, middle panel) and DY406 (IL-6, bottom panel). The graphs show per-group mean serum cytokine concentrations and SEM (standard error of the mean) for each time point.

[0024] FIG. 11 shows immunopotentiating effects of a 502 adjuvant. Anti-MA IgG (pg/ml) response (panel A) and anti-502 antibody response (panel B) by ELISA to TT-SMA vaccine in the presence and absence of alum or entolimod (a varying range from 0 to 20 .mu.g) in pooled sera collected at week 2, 4 and 6 post initial vaccination is shown. Data represent the levels of antibody in the pooled samples from each group (n=5/group).

DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention is also based, in part, on the surprising discovery that flagellin-based agents, including CBLB502 and any of the flagellin-based agents (e.g. agents comprising the sequences of Table 1, including MX-33) described herein, can be mixed with aluminum gels or salts (and, optionally antigens), in ratios well-below the loading/adsorbing capacity of the aluminum gel or salt (e.g. 1:500), and cause a broader, more diverse, more robust and longer lasting immunostimulatory effect than the vaccine comprising the antigen and the aluminum gel or salt alone and/or the adjuvant comprising the aluminum gel or salt alone. The inventors have also surprisingly discovered that the immunostimulatory effect can influence both the T.sub.H1 and T.sub.H2-mediated arms of an immune response. The inventors have also surprisingly discovered that low amounts of flagellin-based agents, including CBLB502 and any of the flagellin-based agents (e.g. agents comprising the sequences of Table 1, including MX-33) relative to antigen are effective for immunostimulation.

[0026] In one aspect, the invention provides a vaccine composition, comprising an adjuvant comprising a flagellin-based agent and an aluminum gel or salt and an antigen and, optionally, an additional adjuvant. In one aspect, the invention provides an adjuvant comprising a flagellin-based agent and an aluminum gel or salt.

[0027] In some embodiments, the described vaccine causes an improvement in adjuvant properties relative to a vaccine comprising the antigen and the aluminum gel or salt alone. In various embodiments, the vaccine and/or adjuvant described herein causes a broader, more diverse, more robust and longer lasting immunostimulatory effect than the vaccine comprising the antigen and the aluminum gel or salt alone (or as compared to the vaccine comprising the antigen and flagellin-based agent alone) and/or the adjuvant comprising the aluminum gel or salt alone (or as compared to the adjuvant comprising the flagellin-based agent alone).

[0028] In some embodiments, the described vaccine and/or described adjuvant causes immunostimulation of one or more of T.sub.H1 and T.sub.H2-mediated immune response. In some embodiments, the described vaccine and/or described adjuvant causes immunostimulation of both of T.sub.H1 and T.sub.H2-mediated immune response. In some embodiments, the described vaccine and/or described adjuvant causes immunostimulation of T.sub.H1-mediated immune response at levels greater than a vaccine comprising the antigen and the aluminum gel or salt alone or an adjuvant comprising the aluminum gel or salt alone.

[0029] T.sub.H1-mediated immune response (or "Type 1 response") largely involves interaction with macrophages and CD8+ T cells and may be linked to interferon-.gamma., TNF-.beta., interleukin-2, and interleukin-10 production. The T.sub.H1-mediated immune response promotes cellular immune system and maximizes the killing efficacy of the macrophages and the proliferation of cytotoxic CD8.sup.+ T cells. The T.sub.H1-mediated immune response also promotes the production of opsonizing antibodies (e.g. IgG, IgM and IgA). The Type 1 cytokine IFN-.gamma. increases the production of interleukin-12 by dendritic cells and macrophages, and via positive feedback, IL-12 stimulates the production of IFN-.gamma. in helper T cells, thereby promoting the T.sub.H1 profile. Interferon-.gamma. also inhibits the production of cytokines such as interleukin-4, a cytokine associated with the Type 2 response, and thus it also acts to preserve its own response.

[0030] T.sub.H2-mediated immune response (or "Type 2 response") largely involves interaction with B-cells, eosinophils, and mast cells and may be linked to interleukin-4, interleukin-5, interleukin-6, interleukin-9, interleukin-10, and interleukin-13. T.sub.H2-mediated immune response promotes humoral immune system and may stimulate B-cells into proliferation, induce B-cell antibody class switching, and increase neutralizing antibody production (e.g. IgG, IgM and IgA as well as IgE antibodies). Other functions of the Type 2 response include promoting its own profile using two different cytokines. Interleukin-4 acts on helper T cells to promote the production of TH2 cytokines (including itself; it is auto-regulatory), while interleukin-10 (IL-10) inhibits a variety of cytokines including interleukin-2 and IFN-.gamma. in helper T cells and IL-12 in dendritic cells and macrophages. The combined action of these two cytokines suggests that once the T cell has decided to produce these cytokines, that decision is preserved (and also encourages other T cells to do the same).

[0031] The division is medically relevant to, inter alia and without wishing to be bound by theory, the fact that alum adjuvants are only effective at inducing a T.sub.H2-mediated response and not a T.sub.H1 mediated response (see, e.g., Smith Korsholm, et al. Immunology. January 2010; 129(1): 75-86, the contents of which are hereby incorporated by reference in their entirety).

[0032] In various embodiments, the stimulation of T.sub.H1 and T.sub.H2-mediated immune responses may be measured by assays known in the art, including a number of antibody surrogate assays (e.g. ELISA and the like). For instance, without wishing to be bound by theory, IgG1 is associated with a T.sub.H2-like response, while a T.sub.H1 response is associated with the induction of IgG2a, IgG2b, and IgG3 antibodies.

[0033] In some embodiments, the described vaccine and/or described adjuvant causes an increase in titer of one or more of IgG1, IgG2a, IgG2b, and IgG3 antibodies (e.g. relative to the adjuvant comprising the aluminum gel or salt or flagellin-based agent alone, or relative to the vaccine comprising the antigen and the aluminum gel or salt alone (or flagellin-based agent) alone)). In some embodiments, the described vaccine and/or described adjuvant causes a relative increase in the titer of all of IgG1, IgG2a, IgG2b, and IgG3 antibodies. In some embodiments, the described vaccine and/or described adjuvant causes a relative increase in the titer of more IgG3 antibodies than the described vaccine and/or described adjuvant in the absence of a flagellin-based agent (or the described vaccine and/or described adjuvant in the absence of an aluminum gel or salt alone).

[0034] Accordingly, in some embodiments, the described vaccine and/or described adjuvant causes a diversified immune response. For example, in some embodiments, the total IgG generated by the described vaccines and/or adjuvants is greater than the described vaccines and/or adjuvants without the flagellin-based agent.

[0035] In some embodiments, the flagellin-based agent may be a flagellin molecule or flagellin-related polypeptide, or variants thereof that have TLR5 agonist activity. The flagellin-based agent may be from various sources, including a variety of Gram-positive and Gram-negative bacterial species. In some embodiments, the flagellin-based agents may have an amino acid sequence that is derived from any of the flagellins from bacterial species that are depicted in, for example, FIG. 7 of U.S. Patent Publication No. 2003/0044429, the contents of which are incorporated herein by reference in their entirety. The flagellin-based agent may have nucleotide sequences related to those encoding the flagellin polypeptides listed in, for example, FIG. 7 of U.S. 2003/0044429, which are publicly available at sources including the NCBI Genbank database.

[0036] The flagellin-based agent may be the major component of bacterial flagellum. The flagellin-based agents may be composed of one, or two, or three, or four, or five, or six, or seven domains or fragments thereof (see, e.g., FIG. 10 of U.S. Pat. No. 8,324,163, the contents of which are incorporated herein by reference in their entirety). The domains may be selected from ND0, ND1, ND2, D3, CD2, CD1, and CDO. Domains 0 (D0), 1 (D1), and 2 (D2) may be discontinuous and may be formed when residues in the amino terminus and carboxy terminus are juxtaposed by the formation of a hairpin structure. The amino and carboxy terminus comprising the D1 and D2 domains may be most conserved, whereas the middle hypervariable domain (D3) may be highly variable. The non-conserved D3 domain may be on the surface of the flagellar filament and may contain the major antigenic epitopes. The potent proinflammatory activity of flagellin may reside in the highly conserved N and CD1 and D2 regions.

[0037] The flagellin-based agents may be from a species of Salmonella, representative examples of which are S. typhimurium and S. dublin (encoded by GenBank Accession Number M84972). The flagellin related-polypeptide may be a fragment, variant, analog, homolog, or derivative of wild type flagellin (SEQ ID NO: 1), or combination thereof. A fragment, variant, analog, homolog, or derivative of flagellin may be obtained by rational-based design based on the domain structure of flagellin and the conserved structure recognized by TLR5.

[0038] The flagellin-based agent may be related to a flagellin polypeptide from any Gram-positive or Gram-negative bacterial species including, but not limited to, the flagellin polypeptides disclosed in U.S. Pat. Pub. 2003/0044429, the contents of which are incorporated herein, and the flagellin peptides corresponding to the Accession numbers listed in the BLAST results shown in FIG. 7 (panels A-F) of U.S. Patent Pub. 2003/0044429, or variants thereof.

[0039] In some embodiments, the flagellin-based agent comprises or consists of any of the polypeptides or nucleic acids encoding said polypeptides listed in Table 1. In some embodiments, the flagellin-based agent is encoded by the nucleotide sequences listed in Table 1. In a further embodiment, the flagellin-based agent comprises the polypeptides listed in Table 1. In some embodiments, the flagellin-based agent comprises one or more of SEQ ID NOs.: 1-252. In some embodiments, the flagellin-based agent comprises a flexible linker. In a further embodiment, the flexible linker comprises SEQ ID NO: 16. In yet a further embodiment, the flexible linker comprises SEQ ID NO: 242.

[0040] In some embodiments, the flagellin-based agent is a variant of SEQ ID NO: 1. In variois embodiments, the flagellin-based agent is not SEQ ID NO: 1.

[0041] In some embodiments, the flagellin-based agent comprises or consists of CBLB502 (SEQ ID NO: 2) or is a variant of CBLB502 (SEQ ID NO: 2). In various embodiments, CBLB502 provides the advantage of, inter alia, removal of epitopes that generate neutralizing anti-flagellin antibodies and therefore allow for the surprising adjuvant properties seen here in combination with alum.

[0042] In some embodiments, the flagellin-based agent comprises mutations in epitopes recognized by neutralizing anti-CBLB502 antibodies. The flagellin-based agent may comprise one or more mutations in the epitopes recognized by neutralizing anti-CBLB502 antibodies which inhibit or abrogate the ability of the antibodies to neutralize the composition. In yet a further embodiment, the flagellin-based agent comprises a truncation and mutations in one or more epitopes. In a further embodiment, the mutations comprise replacement of the epitope residues with alanine. In a further embodiment, the mutated epitopes comprise one or more of the following residues: E153, S444, T154, N440, Q142, F131, D443, N68, T447, S110, Q117, R124, D113, E120, N127, and Q128.

[0043] The flagellin-based agent may comprise insertions, deletions, transposon insertions, and changes to any one of the D0, D1, D2, and the variable D3 domains. The D3 domain may be substituted in part, or in whole, with a hinge or linker polypeptide that allows the D1 and D2 domains to properly fold such that the variant stimulates TLR5 activity.

[0044] In some embodiments, the flagellin-based agent may be a minimal functional core of a flagellin, for example, deleting residues relative to the already shortened CBLB502 molecule. In some embodiments, the flagellin-based agent has altered amino acid identity relative to wild type, including deletions, additions and substitutions, that provide for improved activity. In some embodiments, the flagellin-based agent is derived from CBLB502 (SEQ ID NO: 2). In some embodiments, the flagellin-based agent comprises a truncation in one or more domains. In a further embodiment, the flagellin-based agent comprises a deletion in an N-terminal domain.

[0045] In yet a further embodiment, the flagellin-based agent comprises a deletion in the NDO domain. In yet a further embodiment, the flagellin-based agent comprises a deletion of the entire NDO domain. In a further embodiment, the flagellin-based agent comprises a deletion in a C-terminal domain. In yet another embodiment, the flagellin-based agent comprises a deletion in the CD0 domain. In yet another embodiment, the flagellin-based agent retains amino acids 470-485 of the CD0 domain. In yet a further embodiment, the flagellin-based agent is CBLB502-S33 (SEQ ID NO: 17).

[0046] The flagellin-based agent may comprise at least 10, 11, 12, or 13 of the 13 conserved amino acids shown in FIG. 1A and FIG. 1B (positions 89, 90, 91, 95, 98, 101, 115, 422, 423, 426, 431, 436 and 452). The flagellin may be at least 30-99% identical to amino acids 1-174 and 418-505 of SEQ ID NO: 1.

[0047] In some embodiments, the flagellin-based agent comprises a tag. In yet a further embodiment, the tag is attached to the N-terminus of the flagellin-based agent. In yet another embodiment, the tag is attached to the C-terminus of the flagellin-based agent.

[0048] In some embodiments, the flagellin-based agent comprises a flexible linker. In a further embodiment, the flexible linker comprises SEQ ID NO: 16. In yet a further embodiment, the flexible linker comprises SEQ ID NO:242.

[0049] In various embodiments, the flagellin-based agent is one or more of the flagellin related composition derived from SEQ ID NO: 2. In various embodiments, the flagellin-based agent is one or more of CBLB502-S33ML (SEQ ID NO: 35), CBLB502-485CT (CBLB533, SEQ ID NO: 71), and CBLB502-S33MX (SEQ ID NO: 150).

[0050] In various embodiments, the flagellin-based agent is a flagellin derivative from a thermophilic microorganism. In various embodiments, the flagellin-based agent is a flagellin derivative from a microorganism well-tolerated by human. In some embodiments, the flagellin-based agent is one or more of SEQ ID NOs: 243-252.

[0051] In some embodiments, a variant includes molecules that have TLR5 agonist activity. In some embodiments, a variant includes molecules comprising an amino acid sequence having at least about 70% (e.g.

[0052] about 70%, or about 71%, or about 72%, or about 73%, or about 74%, or about 75%, or about 76%, or about 77%, or about 78%, or about 79%, or about 80%, or about 81%, or about 82%, or about 83%, or about 84%, or about 85%, or about 86%, or about 87%, or about 88%, or about 89%, or about 90%, or about 91%, or about 92%, or about 93%, or about 94%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99%) sequence identity with SEQ ID NO: 1 or SEQ ID NO: 2.

[0053] In some embodiments, the flagellin-based agent comprises or consists of any of the polypeptides or nucleic acids encoding said polypeptides listed in Table 1. In some embodiments, the flagellin-based agent is encoded by the nucleotide sequences listed in Table 1. In a further embodiment, the flagellin-based agent comprises one or more of the polypeptides listed in Table 1. In some embodiments, the flagellin-based agent comprises or consists of polypeptides encoded by either SEQ ID NOs: 69 or 70. In some embodiments, the flagellin-based agent comprises or consists of the polypeptides of SEQ ID NO: 71, "CBLB543". In some embodiments, the flagellin-based agent comprises or consists of polypeptides encoded by either SEQ ID NOs: 149 or 151. In some embodiments, the flagellin-based agent comprises or consists of the polypeptides of SEQ ID NO: 150, "CBLB533".

TABLE-US-00001 TABLE 1 Illustrative Flagellin-Based Agents SEQ DNA/ ID Construct Name PRT Species Sequence 0001 Wild type PRT Salmonella MAQVINTNSLSLLTQNNLNKSQSSLSSAIERLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRN dublin ANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQ- FN GVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNGPKEATVGDLKSSFKNVTGYDTY AAGADKYRVDINSGAVVTDAAAPDKVYVNAANGQLTTDDAENNTAVDLFKTTKSTAGTAEAKAIA GAIKGGKEGDTFDYKGVTFTIDTKTGDDGNGKVSTTINGEKVTLTVADIATGAADVNAATLQSSKN VYTSVVNGQFTFDDKTKNESAKLSDLEANNAVKGESKITVNGAEYTANATGDKITLAGKTMFIDKT ASGVSTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRI EDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLR 0002 CBLB502 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDPMAQVINTNSLSLLTQNNLNKSQSSLSSAIE Sequence RLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSV QATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKI DVKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAI QNRFDSAITNLGNTVTNLNSARSRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLL R 0003 T7 Promoter (forward) DNA Artificial TAATACGACTCACTATAGGGG Sequence 0004 FliC AA74-80 (forward) DNA Artificial ATTGCGCAGACCACTGAAGG Sequence 0005 Thrombin cleavage site PRT Artificial LVPRGS Sequence 0006 Enterokinase cleavage Artificial DDDDK site Sequence 0007 NS (N-terminal spoke PRT Artificial SSGLRINSAKDDA region; Ser32-Ala44) Sequence 0008 CS (C-terminal spoke PRT Artificial EDADYA region; Glu464 to Sequence Ala469) 0009 linker PRT Artificial AASAGAGQGGGGSG Sequence 0010 linker PRT Artificial EGKSSGSGSESKST Sequence 0011 linker PRT Artificial GGGRTSSSAASAGAGQGGGGSG Sequence 0012 linker PRT Artificial GPSG Sequence 0013 linker PRT Artificial GSAGSAAGSGEF Sequence 0014 linker PRT Artificial GSPG Sequence 0015 linker PRT Artificial KESGSVSSEQLAQFRSLD Sequence 0016 linker PRT Artificial SPGISGGGGGILDSMG Sequence 0017 Mutant 33-485 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPSGLRINSAKDDAAGQAIANRFTSNIK Mutant S33 Sequence GLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRV SNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSM GTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLR 0018 Mutant 33-485 DNA Artificial GCAGATTCTGCAGCAGGCTGGTTGATAATCTGGCGCAGGCTAACCAGG Forward Primer Sequence CBLB485 0019 Mutant 33-485 DNA Artificial TCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTT 502 template sequence Sequence 0020 Mutant 33-485 DNA Artificial CCTGGTTAGCCTGCGCCAGATTATCAACCAGCCTGCTGCAGAATCTGC Reverse Primer Sequence CBLB485 0021 Mutant 33-485 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA sequence of 485 Sequence AACTTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTA Mutant (T7 Promoter to GCATGACTGGTGGACAGCAAATGGGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGC Stop) GAAGGATCCGTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATT GCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGC ATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGT GCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCA GGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGG TGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAAC CATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAAT TCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAA GACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTC AAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTAC CAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACT ATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTTGATAA 0022 Mutant 33-485 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPSGLRINSAKDDAAGQAIANRFTSNIK Expressed Mutant 33- Sequence GLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRV 485 SNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSM GTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAG 0023 Mutant 450T PRT Artificial MAQVINTNSLSLLTQNNLNKSQSSLSSAIERLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRN Mutant 506T Sequence ANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFN GVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDA AAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYATEVSN MSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHGMASMTGGQQMGRDLYDDDDKD P 0024 Mutant 450T DNA Artificial ATGGCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGAACAAATCT Mutant 506T Sequence CAGTCCTCACTGAGTTCCGCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAACAGCGCGAA AGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTC AGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAAT GAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAA CTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCG CGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATC CAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGC CTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTA GACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCC ACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAAT TCAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGC GCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGAT TCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCT CTTTACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGACTGGTG GACAGCAAATGGGTCGGGATCTGTACGACGATGACGATAAGGATCCGTAAGTCGACAAGCTT GCG 0025 Mutant 450T DNA Artificial CGAAAGACCATATGGCAGGCCAGGCGATTGC Forward F45CT Sequence 0026 Mutant 450T DNA Artificial CGCAAGCTTGTCGACTTACGGATCCTTATCGTC Reverse R45CT Sequence 0027 Mutant 450T DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAAATAATTTTGTT Sequence of 450T Sequence TAACTTTAAGAAGGAGATATACATATGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAAT construct ATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACT GAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGC CACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCT GGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGA CAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAA AATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGG TGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGA AAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTT CTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAA CCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATA TGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTT CCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTATG GCTAGCATGACTGGTGGACAGCAAATGGGTCGGGATCTGTACGACGATGACGATAAGGATCC GTAAGTCGAC 0028 Mutant 450T PRT Artificial MAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLK Expressed Mutant 450T Sequence SIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNS PGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNT VTNLNSARSRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHGM ASMTGGQQMGRDLYDDDDKDP 0029 Mutant 33GP5 DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC Expressed Mutant 33ML Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTA TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCGGACCATCA GGTCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTT AACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGG TGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAA TGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGT GGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCT TGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAA CGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCG CAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCAT CATCATCATGGTTAA 0030 Mutant 33GPS PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Expressed Mutant 33ML Sequence ATNGTNSDSDLKSIGPSGQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDL QKIDVKSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSAR SRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0031 Mutant 33GP5 DNA Artificial GATATACATATGAGCGGGTTACGGATCAACAG Forward primer FSY3CT Sequence 0032 Mutant 33GP5 DNA Artificial AGATCTCCCGGGGAATTAACATTGAACCC Reverse primer RMIMxN Sequence 0033 Mutant 33GP5 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA sequence of Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG mutant 33GP5 GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTGGACCATCAGGTGAAATTCAGC AACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGT CTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTA CCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTC TGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATC TGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTA AAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAA AACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0034 Mutant 33GP5 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Expressed Mutant Sequence ATGPSGEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFN 33GP5 VNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYATEV- SN MSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0035 Mutant 33ML PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant 330T (Fixed A) Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQ NRFDSAITNLGNTVTNLNSARSRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVP RGSHHHHHHG 0036 Mutant 33ML DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC Mutant 330T (Fixed A) Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTA TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAA ATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAA

GTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTAC CATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCC GGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACG CTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAG TGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACC TTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCA ACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCG CAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCAT CATCATCATGGTTAA 0037 Mutant 33ML DNA Artificial TCTAGACCCGGGAAGTACCGCTAACCCACTGGCTTCAATTG Forward primer F502ML Sequence 0038 Mutant 33ML DNA Artificial CCAGTCATGTCGACTTAACCATGATGATGATGATGATGAG Reverse primer R33CT Sequence 0039 Mutant 33ML DNA Artificial CTCATCATCATCATCATCATGGTTAAGTCGACAAGCTTGCGGCCGCAGAGCTCGC 502 template sequence Sequence 0040 Mutant 33ML DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT 33ML construct Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0041 Mutant 33ML DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC Expressed Mutant 33ML Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTA TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAA ATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAA GTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTAC CATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCC GGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGG TAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTA ATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAG GTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGT TAA 0042 Mutant 33ML PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant 33ML Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0043 Mutant 370T DNA Artificial ATGGCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGAACAAATCT delta NDO mutant based Sequence CAGTCCTCACTGAGTTCCGCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAACGGCGCGAA on CBLB506T AGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTC AGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAAT GAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAA CTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCG CGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATC CAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGC CTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTA GACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCC ACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAAT TCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGC GCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGAT TCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCT CTTTACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGACTGGTG GACAGCAAATGGGTCGGGATCTGTACGACGATGACGATAAGGATCCGTAAGTCGACAAGCTT GCG 0044 Mutant 370T PRT Artificial MAQVINTNSLSLLTQNNLNKSQSSLSSAIERLSSGLRINGAKDDAAGQAIANRFTSNIKGLTQASRN delta NDO mutant based Sequence ANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFN on CBLB506T GVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDA AAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYATEVSN MSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHGMASMTGGQQMGRDLYDDDDKD P 0045 Mutant 370T DNA Artificial CTCTGGTCATATGATCAACAGCGCGAAAGACGATGC Forward F37CT Sequence 0046 Mutant 370T DNA Artificial TCTAGAGTCGACTATTAAGCCATACCATGATGATGATGATGATGAG Reverse R37CT Sequence 0047 Mutant 370T DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAAATAATTTTGTT 370T construct Sequence TAACTTTAAGAAGGAGATATACATATGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGC GATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGA CGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGC GTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTA TCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTA ACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGT GAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAAT GTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATC AATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGC ATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGC CATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATG CTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTT CCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGT TCTCATCATCATCATCATCATGGTATGGCTTAATAGTCGAC 0048 Mutant 370T PRT Artificial MINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATNG Mutant 370T Sequence TNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLG LDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFD SAITNLGNTVTNLNSARSRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSH HHHHHGMA 0049 Mutant 445 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPMAQVINTNSLSLLTQNNLNKSQSSLS 502-SY1 Sequence SAIERLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVR ELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITID LQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSS LGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVL SLLR 0050 Mutant 445 DNA Artificial ATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGACTGGTGGACAGCAAATG 502-SY1 Sequence GGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGCGAAGGATCCGATGGCACAAGTCA TTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGAACAAATCTCAGTCCTCACTGA GTTCCGCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCA GGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAAC GCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAA CCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATC TGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGA CTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTA ACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATG GGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGT ACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATT GATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGTTTT GATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATC GAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCT GGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGCGTTAA 0051 Mutant 445 DNA Artificial GGCAATTCAAAACCGTTTTGATTAAGCCATTACCAACCTTGG Forward Primer Sequence CBLB445 0052 Mutant 445 DNA Artificial CCAAGGTTGGTAATGGCTTAATCAAAACGGTTTTGAATTGCC everse Primer Sequence CBLB445 0053 Mutant 445 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT mutant 445 Sequence AACTTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTA GCATGACTGGTGGACAGCAAATGGGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGC GAAGGATCCGATGGCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCT GAACAAATCTCAGTCCTCACTGAGTTCCGCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAA CAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAG GTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGT GCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAA CGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGA AATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCA GATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGA TGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTG GTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTA CCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTC TGGGGGCAATTCAAAACCGTTTTGATTAA 0054 Mutant 445 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPMAQVINTNSLSLLTQNNLNKSQSSLS mutant 445 Sequence SAIERLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVR ELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITID LQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSS LGAIQNRFD 0055 Mutant 461 DNA Artificial CAATCTGAACTCCGCGCGTTGACGTATCTAAGATGCTGACTATGC Forward Primer Sequence CBLB461 0056 Mutant 461 DNA Artificial GCATAGTCAGCATCTTAGATACGTCAACGCGCGGAGTTCAGATTG Reverse Primer Sequence CBLB461 0057 Mutant 461 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Mutant 461 Sequence AACTTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTA GCATGACTGGTGGACAGCAAATGGGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGC GAAGGATCCGATGGCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCT GAACAAATCTCAGTCCTCACTGAGTTCCGCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAA CAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAG GTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGT GCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAA CGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGA AATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCA GATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGA TGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTG GTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTA CCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTC TGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATC TGAACTCCGCGCGTTGACGTATCTAA 0058 Mutant 461 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPMAQVINTNSLSLLTQNNLNKSQSSLS Mutant 461 Sequence SAIERLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVR ELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITID LQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSS LGAIQNRFDSAITNLGNTVTNLNSAR 0059 Mutant 467 DNA Artificial CGTAGCCGTATCGAAGATGCTTAATAGGCAACGGAAGTTTCTAATATG Forward Primer Sequence CBLB467 0060 Mutant 467 DNA Artificial CATATTAGAAACTTCCGTTGCCTATTAAGCATCTTCGATACGGCTACG Reverse Primer Sequence CBLB467 0061 Mutant 467 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Mutant 467 Sequence AACTTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTA GCATGACTGGTGGACAGCAAATGGGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGC GAAGGATCCGATGGCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCT GAACAAATCTCAGTCCTCACTGAGTTCCGCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAA CAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAG GTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGT GCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAA CGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGA AATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCA GATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGA TGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTG GTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTA CCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTC TGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATC TGAACTCCGCGCGTAGCCGTATCGAAGATGCTTAATAG

0062 Mutant 467 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPMAQVINTNSLSLLTQNNLNKSQSSLS Mutant 467 Sequence SAIERLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVR ELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITID LQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSS LGAIQNRFDSAITNLGNTVTNLNSARSRIEDA 0063 Mutant 4700T DNA Artificial ATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGACTGGTGGACAGCAAATG CBLB502 Sequence GGTCGGGATCTGTACGACGATGACGATAAGGATCCGATGGCACAAGTCATTAATACAAACAG CCTGTCGCTGTTGACCCAGAATAACCTGAACAAATCTCAGTCCTCACTGAGTTCCGCTATTGA GCGTCTGTCCTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATT GCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGC ATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGT GCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCA GGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGG TGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAAC CATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAAT TCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAA GACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTC AAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTAC CAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACT ATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTC TGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGCGTTAA 0064 Mutant 4700T DNA Artificial CGATAAGGATCATATGGCACAAGTCATTAATAC Forward Primer F4700T Sequence 0065 Mutant 4700T DNA Artificial AGATCTGTCGACTTAACCATGATGATGATGATGATGAGAACCCCGCGGAACCAGTGCATAGT Reverse Primer R4700T Sequence CAGCATCTTCGATACG 0066 Mutant 4700T DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Mutant 4700T Sequence AACTTTAAGAAGGAGATATACATATGGCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGA CCCAGAATAACCTGAACAAATCTCAGTCCTCACTGAGTTCCGCTATTGAGCGTCTGTCCTCTG GTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCAC TTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCA GACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTG TTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGC AACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGT CTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATC TGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTT CCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCA GCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCA GTTCGTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAAT ACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCACTGGTTCC GCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0067 Mutant 4700T PRT Artificial MAQVINTNSLSLLTQNNLNKSQSSLSSAIERLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRN Mutant 4700T Sequence ANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFN GVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDA AAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYALVPRG SHHHHHHG 0068 Mutant 4850T DNA Artificial AGATCTCCGCGGAACCAGACCAGCCTGCTGCAGAATCTGC Reverse primer R485M0 Sequence 0069 Mutant 4850T DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA Sequence of Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG 4850T GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTCTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0070 Mutant 4850T DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC Mutant 4850T Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTA TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAA ATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAA GTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTAC CATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCC GGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGG TAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTA ATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTCTGGTTCCGCGGGGTTCTCATCATCAT CATCATCATGGTTAA 0071 Mutant 4850T PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant 4850T Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGLVPRGSHHHHHHG 0072 Mutant 485D DNA Artificial AACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGG DNA template for Sequence GCAATTCAAAACCGTTTTGATTCAGCCATTACCGCCCTTGGCAATACGGTAACCAAT deletion mutations from Mutant 4850T variant 0073 Mutant 485D PRT Artificial NPLASIDSALSKVDAVRSSLGAIQNRFDSAITALGNTVTN PRT sequence for Sequence deletion mutations from Mutant 4850T variant 0074 Mutant 485D DNA Artificial GTTCGTTCTTCTCTGGGGGCAATTGATTCAGCCATTACCGCCCTTG Forward Primer F485D Sequence 0075 Mutant 485D DNA Artificial CAAGGGCGGTAATGGCTGAATCAATTGCCCCCAGAGAAGAACGAAC Reverse Primer R485D Sequence 0076 Mutant 485D DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA Sequence of Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG 4850T_Delta construct GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTGATTCAGCCATTACCGCCCTTG GCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACG GAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTCTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0077 Mutant 485D PRT Artificial MSGLRINSAKDDAAGQIAINRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant 485D (CT_Delta Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV 439-442) KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIDSAITALGNTVTNLNSARSRIEDADYA TEVSNMSKAQILQQAGLVPRGSHHHHHHG 0078 Mutant CGD1 DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC Mutant SY3CT Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTA TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAA ATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAA GTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTAC CATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCC GGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGG TAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCACTGGTTCCGCGG GGTTCTCATCATCATCATCATCATGGTTAA 0079 Mutant CGD1 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant SY3CT Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYALVPRGSHHHHHHG 0080 Mutant CGD1 DNA Artificial ATGAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCCCAATTCTTGTTGAATTAGATGGTGAT GFPuv4 Sequence GTTAATGGGCACAAATTTTCTGTCAGTGGAGAGGGTGAAGGTGATGCAACATACGGAAAACTT ACCCTTAAATTTATTTGCACTACTGGAAAACTACCTGTTCCATGGCCAACACTTGTCACTACTC TGACGTATGGTGTTCAATGCTTTTCCCGTTATCCGGATCATATGAAACGGCATGACTTTTTCAA GAGTGCCATGCCCGAAGGTTATGTACAGGAACGCACTATATCTTTCAAAGATGACGGGAACT ACAAGACGCGTGCTGAAGTCAAGTTTGAAGGTGATACCCTTGTTAATCGTATCGAGTTAAAAG GTATTGATTTTAAAGAAGATGGAAACATTCTCGGACACAAACTCGAGTACAACTATAACTCACA CAATGTATACATCACGGCAGACAAACAAAAGAATGGAATCAAAGCTAACTTCAAAATTCGCCA CAACATTGAAGATGGATCCGTTCAACTAGCAGACCATTATCAACAAAATACTCCAATTGGCGA TGGCCCTGTCCTTTTACCAGACAACCATTACCTGTCGACACAATCTGCCCTTTTGAAAGATCC CAACGAAAAGCGTGACCACATGGTCCTTCTTGAGTTTGTAACTGCTGCTGGGATTACACATGG CATGGATGAACTATACAAA 0081 Mutant CGD1 PRT Artificial MSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTLTY GFPuv4 Sequence GVQCFSRYPDHMKRHDFFKSAMPEGYVQERTISFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFK EDGNILGHKLEYNYNSHNVYITADKQKNGIKANFKIRHNIEDGSVQLADHYQQNTPIGDGPVLLPD NHYLSTQSALLKDPNEKRDHMVLLEFVTAAGITHGMDELYK 0082 Mutant CGD1 DNA Artificial ATGAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCCCAATTCTTGTTGAATTAGATGGTGAT GFPuv4 mutation of wt Sequence GTTAATGGGCACAAATTTTCTGTCAGTGGAGAGGGTGAAGGTGATGCAACATACGGAAAACTT Ndel site ACCCTTAAATTTATTTGCACTACTGGAAAACTACCTGTTCCATGGCCAACACTTGTCACTACTC TGACGTATGGTGTTCAATGCTTTTCCCGTTATCCGGATCACATGAAACGGCATGACTTTTTCAA GAGTGCCATGCCCGAAGGTTATGTACAGGAACGCACTATATCTTTCAAAGATGACGGGAACT ACAAGACGCGTGCTGAAGTCAAGTTTGAAGGTGATACCCTTGTTAATCGTATCGAGTTAAAAG GTATTGATTTTAAAGAAGATGGAAACATTCTCGGACACAAACTCGAGTACAACTATAACTCACA CAATGTATACATCACGGCAGACAAACAAAAGAATGGAATCAAAGCTAACTTCAAAATTCGCCA CAACATTGAAGATGGATCCGTTCAACTAGCAGACCATTATCAACAAAATACTCCAATTGGCGA TGGCCCTGTCCTTTTACCAGACAACCATTACCTGTCGACACAATCTGCCCTTTTGAAAGATCC CAACGAAAAGCGTGACCACATGGTCCTTCTTGAGTTTGTAACTGCTGCTGGGATTACACATGG CATGGATGAACTATACAAATAA 0083 Mutant CGD1 DNA Artificial TCTAGACGGCCGATCTCAGGTAAGAATGGAATCAAAGCTAACTTCAAAATTCGC Forward primer FCGFP Sequence 0084 Mutant CGD1 PRT Artificial NVYIPISGKNGIKANFKIRH PRT altered GFPuv4 Sequence sequence 0085 Mutant CGD1 DNA Artificial AGATCTCCGCGGTTTGTATAGTTCATCCATGCCATGTGTAATCCC Reverse RCGFP Sequence 0086 Mutant CGD1 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA Sequence of CGD1 Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG onstruct GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCACTGGTTCCGCCGATCTCAGGTAAGAATGGAATCAAAGCTAACTTCAAAATTCGC CACAACATTGAAGATGGATCCGTTCAACTAGCAGACCATTATCAACAAAATACTCCAATTGGC GATGGCCCTGTCCTTTTACCAGACAACCATTACCTGTCGACACAATCTGCCCTTTTGAAAGAT CCCAACGAAAAGCGTGACCACATGGTCCTTCTTGAGTTTGTAACTGCTGCTGGGATTACACAT GGCATGGATGAACTATACAAACCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0087 Mutant CGD1 DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC Expressed Mutant CGD1 Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTA TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAA ATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAA GTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTAC CATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCC GGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGG TAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCACTGGTTCCGCCG ATCTCAGGTAAGAATGGAATCAAAGCTAACTTCAAAATTCGCCACAACATTGAAGATGGATCC

GTTCAACTAGCAGACCATTATCAACAAAATACTCCAATTGGCGATGGCCCTGTCCTTTTACCA GACAACCATTACCTGTCGACACAATCTGCCCTTTTGAAAGATCCCAACGAAAAGCGTGACCAC ATGGTCCTTCTTGAGTTTGTAACTGCTGCTGGGATTACACATGGCATGGATGAACTATACAAA CCGCGGGGTTCTCATCATCATCATCATCATGGTTAA 0088 Mutant CGD1 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Expressed Mutant CGD1 Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYALVPPISGKNGIKANFKIRHNIEDGSVQLADHYQQNTPIGDGPVLLPDNHYLSTQSALLKDPNE KRDHMVLLEFVTAAGITHGMDELYKPRGSHHHHHHG 0089 Mutant CPM194 DNA Artificial ATGAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGT Mutant CPM194 Sequence TCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTA ACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCATCCCCGGGAAGCGG GTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTT CTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGA CCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTT CAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAA CGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCT CAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTCTGGTTCCGCGGGGTTCTCA TCATCATCATCATCATGGTTAA 0090 Mutant CPM194 PRT Artificial MSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYASPGSGLRIN Mutant CPM194 Sequence SAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNS DSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGLVPRGSHHHHHHG 0091 Mutant CPM194 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Mutant CPM194 Sequence AACTTTAAGAAGGAGATATACATATGAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATT GTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCAT TACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTG ACTATGCATCCCCGGGAAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAA CGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGC AGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAAT CTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAAT TTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATG GTCTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0092 Mutant CPM194 DNA Artificial TCTAGACATATGAGTACCGCTAACCCACTGGCTTCAATTG Forward primer FCD1 Sequence 0093 Mutant CPM194 DNA Artificial GCTTCCCGGGGATGCATAGTCAGCATCTTCGATACGGC Reverse primer RCD1J Sequence 0094 Mutant CPM194 DNA Artificial GCATCCCCGGGAAGCGGGTTACGGATCAACAGCG Forward primer FND1J Sequence 0095 Mutant CPM194 DNA Artificial AGATCTCCGCGGAACCAGACCATCGTTAGCACCAACCTGGATTTTCATCT Reverse primer RND1 Sequence 0096 Mutant CPM217 DNA Artificial ATGAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGT Mutant CPM217 Sequence TCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTA ACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCATCCCCGGGAAGCGG GTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTT CTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGA CCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTT CAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAA CGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCT CAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCT GCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATCTGGTTCCGCGGGG TTCTCATCATCATCATCATCATGGTTAA 0097 Mutant CPM217 PRT Artificial MSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYASPGSGLRIN Mutant CPM217 Sequence SAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNS DSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDG FNVNLVPRGSHHHHHHG 0098 Mutant CPM217 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Mutant CPM217 Sequence AACTTTAAGAAGGAGATATACATATGAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATT GTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCAT TACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTG ACTATGCATCCCCGGGAAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCA GGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAA CGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGC AGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAAT CTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAAT TTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATG GTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCA ATGTTAATCTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0099 Mutant CPM217 DNA Artificial AGATCTCCGCGGAACCAGATTAACATTGAACCCATCAAGGCCAAG Reverse primer Sequence RCPM217 0100 Mutant GD1G DNA Artificial CCCGTTATCCGGATCACATGAAACGGCATGACTTTTTC Forward Primer FGFP77 Sequence 0101 Mutant GD1G DNA Artificial GAAAAAGTCATGCCGTTTCATGTGATCCGGATAACGGG Reverse Primer RGFP77 Sequence 0102 Mutant GD1G DNA Artificial CTGTTCCATGGCCAACACTTG FGFP54 Sequence 0103 Mutant GD1G DNA Artificial TCTAGACATATGAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCC Forward primer FNGFP Sequence 0104 Mutant GD1G DNA Artificial GGCCTATGCGGCCGCAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCCCAATTCTTGTTGAA altered GFP DNA Sequence sequence 0105 Mutant GD1G DNA Artificial AGATCTATTAATGCGGCCTGATAGGCCTTGTTTGTCTGCCGTGATGTATACATTGTG Reverse RNGFP Sequence 0106 Mutant GD1G PRT Artificial SHNVYITADKQGLSGRNM altered GFP PRT Sequence sequence 0107 Mutant GD1G DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA Sequence of GD1G Sequence AACTTTAAGAAGGAGATATACATATGAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCCCAA construct TTCTTGTTGAATTAGATGGTGATGTTAATGGGCACAAATTTTCTGTCAGTGGAGAGGGTGAAG GTGATGCAACATACGGAAAACTTACCCTTAAATTTATTTGCACTACTGGAAAACTACCTGTTCC ATGGCCAACACTTGTCACTACTCTGACGTATGGTGTTCAATGCTTTTCCCGTTATCCGGATCA CATGAAACGGCATGACTTTTTCAAGAGTGCCATGCCCGAAGGTTATGTACAGGAACGCACTAT ATCTTTCAAAGATGACGGGAACTACAAGACGCGTGCTGAAGTCAAGTTTGAAGGTGATACCCT TGTTAATCGTATCGAGTTAAAAGGTATTGATTTTAAAGAAGATGGAAACATTCTCGGACACAAA CTCGAGTACAACTATAACTCACACAATGTATACATCACGGCAGACAAACAAGGCCTATCAGGC CGCATTATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTG CTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCA TTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTG CGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAG GATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGT GTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAAC CATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAAT TCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGC AGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAA TACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCACTGGTTC CGCCGATCTCAGGTAAGAATGGAATCAAAGCTAACTTCAAAATTCGCCACAACATTGAAGATG GATCCGTTCAACTAGCAGACCATTATCAACAAAATACTCCAATTGGCGATGGCCCTGTCCTTT TACCAGACAACCATTACCTGTCGACACAATCTGCCCTTTTGAAAGATCCCAACGAAAAGCGTG ACCACATGGTCCTTCTTGAGTTTGTAACTGCTGCTGGGATTACACATGGCATGGATGAACTAT ACAAACCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0108 Mutant GD1G DNA Artificial ATGAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCCCAATTCTTGTTGAATTAGATGGTGAT Expressed Mutant Sequence GTTAATGGGCACAAATTTTCTGTCAGTGGAGAGGGTGAAGGTGATGCAACATACGGAAAACTT D1G ACCCTTAAATTTATTTGCACTACTGGAAAACTACCTGTTCCATGGCCAACACTTGTCACTACTC TGACGTATGGTGTTCAATGCTTTTCCCGTTATCCGGATCACATGAAACGGCATGACTTTTTCAA GAGTGCCATGCCCGAAGGTTATGTACAGGAACGCACTATATCTTTCAAAGATGACGGGAACT ACAAGACGCGTGCTGAAGTCAAGTTTGAAGGTGATACCCTTGTTAATCGTATCGAGTTAAAAG GTATTGATTTTAAAGAAGATGGAAACATTCTCGGACACAAACTCGAGTACAACTATAACTCACA CAATGTATACATCACGGCAGACAAACAAGGCCTATCAGGCCGCATTATGAGCGGGTTACGGA TCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATC AAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGA AGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCA CTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGG AAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACA ACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAA TTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACC CACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAA TTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCG CGCGTAGCCGTATCGAAGATGCTGACTATGCACTGGTTCCGCCGATCTCAGGTAAGAATGGA ATCAAAGCTAACTTCAAAATTCGCCACAACATTGAAGATGGATCCGTTCAACTAGCAGACCAT TATCAACAAAATACTCCAATTGGCGATGGCCCTGTCCTTTTACCAGACAACCATTACCTGTCG ACACAATCTGCCCTTTTGAAAGATCCCAACGAAAAGCGTGACCACATGGTCCTTCTTGAGTTT GTAACTGCTGCTGGGATTACACATGGCATGGATGAACTATACAAACCGCGGGGTTCTCATCAT CATCATCATCATGGTTAA 0109 Mutant GD1G PRT Artificial MSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTLTY Expressed Mutant Sequence GVQCFSRYPDHMKRHDFFKSAMPEGYVQERTISFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFK GD1G EDGNILGHKLEYNYNSHNVYITADKQGLSGRIMSGLRINSAKDDAAGQAIANRFTSNIKGLTQASR NANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQF NGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGSTANPLASIDSALSKVDAV RSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYALVPPISGKNGIKANFKIRHNIEDGSVQLAD HYQQNTPIGDGPVLLPDNHYLSTQSALLKDPNEKRDHMVLLEFVTAAGITHGMDELYKPRGSHHH HHHG 0110 Mutant MF227C DNA Artificial CTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTACA mutant 4700T template Sequence TTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTG 0111 Mutant MF2270 PRT Artificial LGLDGFNVNSPGISGGGGGITLINEDAAAAKKSTANPLASI mutant 4700T template Sequence 0112 Mutant MF227C DNA Artificial AGATCTCCGCGGAACCAGTAAAGAGAGGACGTTTTGCGGAACCTGGTTTGCATAGTCAGCAT Reverse Primer R2YY Sequence CTTCGATACG 0113 Mutant MF227C DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA sequence of Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG Mutant MF227C GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCAT CATCATCATCATGGTTAAGTCGAC 0114 Mutant MF227C DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC Mutant MF227C Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTA TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAA ATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAA GTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTAC CATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCC GGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGG TAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAAACCAGGTTCCG CAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAA 0115 Mutant MF2270 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant MF2270 Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYANQVPQNVLSLLVPRGSHHHHHHG 0116 Mutant MF227N DNA Artificial AGATCTCCCGGGGAACCATCGTTAGCACCAACCTGGATTTTC Reverse Primer Sequence RMF227N 0117 Mutant MF227N DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT

DNA sequence of Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG mutant MF227N GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAA AAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCA ACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTAT GCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTG GCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCA TCATCATCATCATGGTTAAGTCGAC 0118 Mutant MF227N DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC mutant MF227N Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTA TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAA ATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAA GTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTTCCCCGGGAAG TACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTC TCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAA TCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTC TAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGC AAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAA 0119 Mutant MF227N PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ mutant MF227N Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGSPGSTANPLA SIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYATEVSNMSKAQILQQAGT SVLAQANQVPQNVLSLLVPRGSHHHHHHG 0120 Mutant MF233 DNA Artificial AGATCTCCGCGGAACCAGCAGGTTATTCTGGGTCAACAGCGACAGGCTGTTTGTATTAATGA Reverse primer RMF233 Sequence CTTGTGCATAGTCAGCATCTTCGATACG 0121 Mutant MF233 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA Sequence of Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG construct MF233 GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGCTGGTT CCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0122 Mutant MF233 DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC MF233 Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTA TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAA ATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAA GTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTAC CATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCC GGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGG TAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCACAAGTCATTAATA CAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGCTGGTTCCGCGGGGTTCTCATCATCAT CATCATCATGGTTAA 0123 Mutant MF233 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ MF233 Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYAQVINTNSLSLLTQNNLLVPRGSHHHHHHG 0124 Mutant MF471 DNA Artificial GCTGACTATGCAACGGCAGTTTCTGCTATGTCTGCAGCGCAGATTCTGC Forward primer F471-77 Sequence 0125 Mutant MF471 DNA Artificial GCAGAATCTGCGCTGCAGACATAGCAGAAACTGCCGTTGCATAGTCAGC Reverse Primer R471-77 Sequence 0126 Mutant MF471 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA Sequence of Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG construct MF471 GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGCAGTTTCTGCTATGTCTGCAGCGCAGATTCTGCAGCAGGCTGGTCTGGT TCCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0127 Mutant MF471 DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC MF471 Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTA TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAA ATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAA GTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTAC CATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCC GGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGG TAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGCAGTTTCT GCTATGTCTGCAGCGCAGATTCTGCAGCAGGCTGGTCTGGTTCCGCGGGGTTCTCATCATCA TCATCATCATGGTTAA 0128 Mutant MF471 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ MF471 Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATAVSAMSAAQILQQAGLVPRGSHHHHHHG 0129 Mutant MF479 DNA Artificial GTTTCTAATATGTCTAAAGCGGCGATTCTGGGAGCGGCTGGTCTGGTTCCGCGG Forward primer F479-83 Sequence 0130 Mutant MF479 DNA Artificial CCGCGGAACCAGACCAGCCGCTCCCAGAATCGCCGCTTTAGACATATTAGAAAC Reverse Primer R479-83 Sequence 0131 Mutant MF479 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA Sequence of Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG construct MF479 GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGGCGATTCTGGGAGCGGCTGGTCTGGT TCCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0132 Mutant MF479 DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC Mutant MF479 Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTA TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAA ATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAA GTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTAC CATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCC GGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGG TAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTA ATATGTCTAAAGCGGCGATTCTGGGAGCGGCTGGTCTGGTTCCGCGGGGTTCTCATCATCAT CATCATCATGGTTAA 0133 Mutant MF479 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant MF479 Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAAILGAAGLVPRGSHHHHHHG 0134 Mutant N45 DNA Artificial TCTAGAGGATCCGGCAGGCCAGGCG Forward primer N45_F Sequence 0135 Mutant N45 DNA Artificial CGCAAGCTTGTCGACTTAACGC Reverse R502D0 Sequence 0136 Mutant N45 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA sequence of Sequence AACTTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTA Mutant N45 GCATGACTGGTGGACAGCAAATGGGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGC GAAGGATCCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTC AGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAAT GAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAA CTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCG CGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATC CAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGC CTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTA GACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCC ACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAAT TCAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGC GCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGAT TCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCT CTTTACTGCGTTAAGTCGACAAGCTTGCGG 0137 Mutant N45 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPAGQAIANRFTSNIKGLTQASRNAND Mutant N45 Sequence GISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKV LSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAK KSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYATEVSNMSKA QILQQAGTSVLAQANQVPQNVLSLLR 0138 Mutant NGD1 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA Sequence of NGD1 Sequence AACTTTAAGAAGGAGATATACATATGAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCCCAA construct TTCTTGTTGAATTAGATGGTGATGTTAATGGGCACAAATTTTCTGTCAGTGGAGAGGGTGAAG GTGATGCAACATACGGAAAACTTACCCTTAAATTTATTTGCACTACTGGAAAACTACCTGTTCC ATGGCCAACACTTGTCACTACTCTGACGTATGGTGTTCAATGCTTTTCCCGTTATCCGGATCA CATGAAACGGCATGACTTTTTCAAGAGTGCCATGCCCGAAGGTTATGTACAGGAACGCACTAT ATCTTTCAAAGATGACGGGAACTACAAGACGCGTGCTGAAGTCAAGTTTGAAGGTGATACCCT TGTTAATCGTATCGAGTTAAAAGGTATTGATTTTAAAGAAGATGGAAACATTCTCGGACACAAA CTCGAGTACAACTATAACTCACACAATGTATACATCACGGCAGACAAACAAGGCCTATCAGGC CGCATTATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTG CTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCA TTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTG CGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAG GATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGT GTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAAC CATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAAT TCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGC AGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAA TACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCACTGGTTC CGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0139 Mutant NGD1 DNA Artificial ATGAGTAAAGGAGAAGAACTTTTCACTGGAGTTGTCCCAATTCTTGTTGAATTAGATGGTGAT Expressed Mutant 5Y3- Sequence GTTAATGGGCACAAATTTTCTGTCAGTGGAGAGGGTGAAGGTGATGCAACATACGGAAAACTT GFP ACCCTTAAATTTATTTGCACTACTGGAAAACTACCTGTTCCATGGCCAACACTTGTCACTACTC TGACGTATGGTGTTCAATGCTTTTCCCGTTATCCGGATCACATGAAACGGCATGACTTTTTCAA GAGTGCCATGCCCGAAGGTTATGTACAGGAACGCACTATATCTTTCAAAGATGACGGGAACT ACAAGACGCGTGCTGAAGTCAAGTTTGAAGGTGATACCCTTGTTAATCGTATCGAGTTAAAAG GTATTGATTTTAAAGAAGATGGAAACATTCTCGGACACAAACTCGAGTACAACTATAACTCACA CAATGTATACATCACGGCAGACAAACAAGGCCTATCAGGCCGCATTATGAGCGGGTTACGGA TCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATC AAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGA AGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCA CTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGG AAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACA ACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAA TTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACC CACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAA TTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCG CGCGTAGCCGTATCGAAGATGCTGACTATGCACTGGTTCCGCGGGGTTCTCATCATCATCAT

CATCATGGTTAA 0140 Mutant NGD1 PRT Artificial MSKGEELFTGVVPILVELDGDVNGHKFSVSGEGEGDATYGKLTLKFICTTGKLPVPWPTLVTTLTY Expressed Mutant SY3- Sequence GVQCFSRYPDHMKRHDFFKSAMPEGYVQERTISFKDDGNYKTRAEVKFEGDTLVNRIELKGIDFK GFP/Mutant NGD1 EDGNILGHKLEYNYNSHNVYITADKQGLSGRIMSGLRINSAKDDAAGQAIANRFTSNIKGLTQASR NANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQF NGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGSTANPLASIDSALSKVDAV RSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDADYALVPRGSHHHHHHG 0141 Mutant S33 DNA Artificial TCTAGAGGATCCGTCTGGTCTGCGTATCAACAGCGC Forward F502_533 Sequence 0142 Mutant S33 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA sequence of Sequence AACTTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTA Mutant S33 GCATGACTGGTGGACAGCAAATGGGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGC GAAGGATCCGTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATT GCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGC ATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGT GCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCA GGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGG TGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAAC CATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAAT TCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAA GACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTC AAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTAC CAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACT ATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTC TGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGCGTTAAGTCGAC 0143 Mutant S33 DNA Artificial ATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGACTGGTGGACAGCAAATG Mutant S33 Sequence GGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGCGAAGGATCCGTCTGGTCTGCGTA TCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATC AAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGA AGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCA CTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGG AAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACA ACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAA TTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTG GTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAA AGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCT TCTCTGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACC AATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATG TCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCC GCAAAACGTCCTCTCTTTACTGCGTTAA 0144 Mutant S33 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPSGLRINSAKDDAAGQAIANRFTSNIK Mutant S33 Sequence GLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRV SNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSM GTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLR 0145 Mutant SY3CT DNA Artificial AGATCTCCGCGGAACCAGTGCATAGTCAGCATCTTCGATACGGC Reverse primer RSY3CT Sequence 0146 Mutant SY3CT DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA Sequence of Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG SY3CT construct GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0147 Mutant SY3CT DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC Expressed Mutant Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTA SY3CT TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAA ATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAA GTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTAC CATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCC GGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGG TAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCACTGGTTCCGCGG GGTTCTCATCATCATCATCATCATGGTTAA 0148 Mutant SY3CT PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Expressed Mutant Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV SY3CT KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRI- ED ADYALVPRGSHHHHHHG 0149 Mutant 33MX DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC Mutant 33MX Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTGCAGACGGCATTTCTA TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTGCCGGGGCTAACGCTGATGCCGCTCTGAAAGCTATCCAGGCTGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTCAGCAGACTCAAGCTGCCGCTGTTAA AGTCCTGTCTCAGGACAACGCAATGGCAATCCAGGTTGGTGCTAACGATGGTGCCGCTATTA CCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCC CGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGG TAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTC AAATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAG GTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGT TAA 0150 Mutant 33MX PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNAADGISIAQTTEGALNEINNNLQRVRELSVQA Mutant 33MX Sequence TAGANADAALKAIQAEIQQRLEEIDRVSQQTQAAAVKVLSQDNAMAIQVGANDGAAITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSQMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0151 Mutant 33MX DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA sequence of 33MX Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTGCAGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACA ACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTGCCGGGGCTAACGCTGATGC CGCTCTGAAAGCTATCCAGGCTGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTCA GCAGACTCAAGCTGCCGCTGTTAAAGTCCTGTCTCAGGACAACGCAATGGCAATCCAGGTTG GTGCTAACGATGGTGCCGCTATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCC TTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTG CATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAG CCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGAT GCTGACTATGCAACGGAAGTTTCTCAAATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACT TCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGG TTCTCATCATCATCATCATCATGGTTAAGTCGAC 0152 Mutant 485MX DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA Sequence of Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG 85MX construct GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTGCAGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACA ACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTGCCGGGGCTAACGCTGATGC CGCTCTGAAAGCTATCCAGGCTGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTCA GCAGACTCAAGCTGCCGCTGTTAAAGTCCTGTCTCAGGACAACGCAATGGCAATCCAGGTTG GTGCTAACGATGGTGCCGCTATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCC TTGATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTG CATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAG CCATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGAT GCTGACTATGCAACGGAAGTTTCTCAAATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTCT GGTTCCGCGGGGTTCTCATCATCATCATCATCATGGTTAAGTCGAC 0153 Mutant 485MX DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC 485MX construct Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTGCAGACGGCATTTCTA TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTGCCGGGGCTAACGCTGATGCCGCTCTGAAAGCTATCCAGGCTGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTCAGCAGACTCAAGCTGCCGCTGTTAA AGTCCTGTCTCAGGACAACGCAATGGCAATCCAGGTTGGTGCTAACGATGGTGCCGCTATTA CCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCC CGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGG TAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTC AAATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTCTGGTTCCGCGGGGTTCTCATCATCAT CATCATCATGGTTAA 0154 Mutant 485MX PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNAADGISIAQTTEGALNEINNNLQRVRELSVQA 485MX construct Sequence TAGANADAALKAIQAEIQQRLEEIDRVSQQTQAAAVKVLSQDNAMAIQVGANDGAAITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSQMSKAQILQQAGLVPRGSHHHHHHG 0155 Mutant MIM4 DNA Artificial ATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGACTGGTGGACAGCAAATG CBLB502 variant Sequence GGTCGGGATCTGTACGACGATGACGATAAGGATCCGATGGCACAAGTCATTAATACAAACAG CCTGTCGCTGTTGACCCAGAATAACCTGCAGAAATCTCAGTCCTCACTGAGTTCCGCTATTGA GCGTCTGTCCTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATT GCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGC ATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGT GCGTGAGTTGTCTGTTCAGGCCACTCAAGGGACTAACTCTGATTCCGATCTGAAATCTATCCA GGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTCAGCAGACTCAATTTAACGG TGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAAC CATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAAT TCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAA GACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTC AAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGTTTTGATTCAGCCATTAC CAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACT ATGCAACGGAAGTTTCTCAAATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTC TGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGCGTTAA 0156 Mutant MIM4 DNA Artificial AACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGG Primers design (for Sequence GCAATTCAAAACCGTTTTGATTCAGCCATTACCGCCCTTGGCGCTACGGTAACCGCTCTGGC deletion aa Gln439; CTCCGCGCGTAGCGCTATCGAAGATGCTGACTATGCAACGGAAGTTTCTCAAATG Asn440; Arg441; Phe442): 0157 Mutant MIM4 PRT Artificial NPLASIDSALSKVDAVRSSLGAIQNRFDSAITALGATVTALASARSAIEDADYATEVSNM Primers design (for Sequence deletion aa Gln439; Asn440; Arg441; Phe442): 0158 Mutant MIM4 DNA Artificial GCAGTTCGTTCTTCTCTGGGGGCAATTGATTCAGCCATTACCGCCCTTGG Forward Primer MIM4 Sequence 0159 Mutant MIM4 DNA Artificial CCAAGGGCGGTAATGGCTGAATCAATTGCCCCCAGAGAAGAACGAACTGC Reverse Primer MIM4 Sequence 0160 Mutant MIM4 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAAATAATTTTGTT MIM4 Sequence TAACTTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTA GCATGACTGGTGGACAGCAAATGGGTCGGGATCTGTACGACGATGACGATAAGGATCCGAT GGCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGAACAAATCTCA GTCCTCACTGAGTTCCGCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAACAGCGCGAAAG ACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAG GCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGA AATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACT CTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCG TTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCA GGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCT TGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAG ACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCA CTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATT GATTCAGCCATTACCGCCCTTGGCGCTACGGTAACCGCTCTGGCCTCCGCGGCTAGCCGTAT CGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGC TGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGCGTTA A 0161 Mutant MIM4 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDPMAQVINTNSLSLLTQNNLNKSQSSLSSAIE MIM4 Sequence RLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSV QATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKI

DVKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAI DSAITALGATVTALASAASRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLR 0162 Mutant MIM5 DNA Artificial AACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGG Primers design Sequence GCAATTGCAAAGGCTTTTGATTCAGCCATTACCGCCCTTGGCGCTACGGTAACCGCTCTGGC (mutations Gln439Ala; CTCCGCGCGTAGCGCTATCGAAGATGCTGACTATGCAACGGAAGTTTCTCAAATG Asn440Lys; Arg441Ala): 0163 Mutant MIM5 PRT Artificial NPLASIDSALSKVDAVRSSLGAIAKAFDSAITALGATVTALASARSAIEDADYATEVSNM Primers design Sequence (mutationsGln439Ala; Asn440Lys;Arg441Ala): 0164 Mutant MIM5 DNA Artificial CGTTCTTCTCTGGGGGCAATTGCAAAGGCTTTTGATTCAGCCATTACCGC Forward Primer MIM5 Sequence 0165 Mutant MIM5 DNA Artificial GCGGTAATGGCTGAATCAAAAGCCTTTGCAATTGCCCCCAGAGAAGAACG Reverse Primer MIM5 Sequence 0166 Mutant MIM5 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAAATAATTTTGTT MIM5 Sequence TAACTTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTA GCATGACTGGTGGACAGCAAATGGGTCGGGATCTGTACGACGATGACGATAAGGATCCGAT GGCACAAGTCATTAATACAAACAGCCTGTCGCTGTTGACCCAGAATAACCTGAACAAATCTCA GTCCTCACTGAGTTCCGCTATTGAGCGTCTGTCCTCTGGTCTGCGTATCAACAGCGCGAAAG ACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAG GCTTCCCGTAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGA AATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACT CTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCG TTTCTAATCAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCA GGTTGGTGCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCT TGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAG ACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCA CTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATT GCAAAGGCTTTTGATTCAGCCATTACCGCCCTTGGCGCTACGGTAACCGCTCTGGCCTCCGC GGCTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGAT TCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCT CTTTACTGCGTTAA 0167 Mutant MIM5 PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDDDDKDPMAQVINTNSLSLLTQNNLNKSQSSLSSAIE MIM5 Sequence RLSSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSV QATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKI DVKSLGLDGFNVNSPGISGGGGGILDSMGTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAI AKAFDSAITALGATVTALASAASRIEDADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLR 0168 Mutant MIMX DNA Artificial ATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTAGCATGACTGGTGGACAGCAAATG Mutant 33MIMX Sequence GGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGCGAAGGATCCGTCTGGTCTGCGTA TCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATC AAAGGTCTGACTCAGGCTTCCCGTAACGCTGCAGACGGCATTTCTATTGCGCAGACCACTGA AGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCA CTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGG AAGAAATCGATCGCGTTTCTAATCAGACTCAAGCTAACGGTGTTAAAGTCCTGTCTCAGGACA ACGCAATGAAAATCCAGGTTGGTGCTAACGATGGTGCCGCTATTACCATCGATCTGCAAAAAA TTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCCGGGAATTTCCGGTGGTG GTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGAAGACGCTGCCGCAGCCAAGAAA AGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCT TCTCTGGGGGCAATTCAAGCTCGTTTTGCCGCGGCCATTGCTAACCTTGGCAATACGGTAAC CAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTAATAT GTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTC CGCAAAACGTCCTCTCTTTACTGCGTTAA 0169 Mutant MIMX PRT Artificial MRGSHHHHHHGMASMTGGQQMGRDLYDLVPRGSAKDPSGLRINSAKDDAAGQAIANRFTSNIK MIMX Sequence GLTQASRNAADGISIAQTTEGALNEINNNLQRVRELSVQATNGTNSDSDLKSIQDEIQQRLEEIDRV SNQTQANGVKVLSQDNAMKIQVGANDGAAITIDLQKIDVKSLGLDGFNVNSPGISGGGGGILDSM GTLINEDAAAAKKSTANPLASIDSALSKVDAVRSSLGAIQARFAAAIANLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLR 0170 Mutant MIMX DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA sequence of Sequence AACTTTAAGAAGGAGATATACATATGCGGGGTTCTCATCATCATCATCATCATGGTATGGCTA 33MIMx GCATGACTGGTGGACAGCAAATGGGTCGGGATCTGTACGACCTGGTTCCGCGCGGTAGCGC GAAGGATCCGTCTGGTCTGCGTATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATT GCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTGCAGACGG CATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGT GCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCA GGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAAGCTAACGG TGTTAAAGTCCTGTCTCAGGACAACGCAATGAAAATCCAGGTTGGTGCTAACGATGGTGCCG CTATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAA TTCCCCGGGAATTTCCGGTGGTGGTGGTGGAATTCTAGACTCCATGGGTACATTAATCAATGA AGACGCTGCCGCAGCCAAGAAAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGT CAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAGCTCGTTTTGCCGCGGCCATT GCTAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGA CTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGT TCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGCGTTAAGTCGAC 0171 Mutant MIXC DNA Artificial AGATCTGTCGACTTAACCATGATGATGATGATGATGAGAACCCCGCGGAACCAGTAAAGAGA Reverse primer RMIXC Sequence GGACGTTTTGCGGAACC 0172 Mutant MIXC DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA sequence of MIXC Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAGCTCGTTTTGCCGCGGCC ATTGCTAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0173 Mutant MIXC PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ MIXC Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQARFAAAIANLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0174 Mutant MIXN DNA Artificial AGATCTCATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGC Forward primer FMIMxN Sequence 0175 Mutant MIXN DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT DNA sequence of MIX.N Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTGCAGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACA ACAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCC GATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAAT CAGACTCAAGCTAACGGTGTTAAAGTCCTGTCTCAGGACAACGCAATGAAAATCCAGGTTGGT GCTAACGATGGTGCCGCTATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTT GATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCA TTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCC ATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0176 Mutant MIXN PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNAADGISIAQTTEGALNEINNNLQRVRELSVQA Expressed Mutant MIX.N Sequence TNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQANGVKVLSQDNAMKIQVGANDGAAITIDLQKIDVK SLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIEDA DYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0177 Mutants MIM1; MIM2 DNA Artificial AACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGG and MIM3 Sequence GCAATTCAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCAATCTGAACT 502 Mutants MIM1; CCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTCAAATGTCTAAAGCG MIM2 and MIM3- CAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGT terminal part of CCTCTCTTTACTGCGTTAA CBLB502 0178 Mutants MIM1; MIM2 DNA Artificial ATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGAT and MIM3 Sequence Primers design (mutant MIM1) 0179 Mutants MIM1; MIM2 PRT Artificial ITNLGNTVTNLNSARSRIED and MIM3 Sequence Primers design (mutant MIM1) 0180 Mutants MIM1; MIM2 DNA Artificial CCTTGGCAATACGGTAACCGCTCTGGCCTCCGCGCGTAGCCGTATC and MIM3 Sequence Forward Primer 455-57 0181 Mutants MIM1; MIM2 DNA Artificial GATACGGCTACGCGCGGAGGCCAGAGCGGTTACCGTATTGCCAAGG and MIM3 Sequence Reverse Primer 455-57 0182 Mutants MIM1; MIM2 DNA Artificial ACGGTAACCGCTCTGGCCTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAA and MIM3 Sequence Primers design (mutant MIM2_MIM1 plus R460A) 0183 Mutants MIM1; MIM2 PRT Artificial TVTALASARSRIEDADYATE and MIM3 Sequence Primers design (mutant MIM2_MIM1 plus R460A) 0184 Mutants MIM1; MIM2 DNA Artificial GCTCTGGCCTCCGCGGCTAGCCGTATCGAAGATG and MIM3 Sequence Forward Primer 460 0185 Mutants MIM1; MIM2 DNA Artificial CATCTTCGATACGGCTAGCCGCGGAGGCCAGAGC and MIM3 Sequence Reverse Primer 460 0186 Mutants MIM1; MIM2 DNA Artificial CAAAACCGTTTTGATTCAGCCATTACCAACCTTGGCAATACGGTAACCGCTCTGGCCTCC and MIM3 Sequence Primers design (mutant MIM3_MIM2 plus N448A; N451A) 0187 Mutants MIM1; MIM2 PRT Artificial QNRFDSAITNLGNTVTALAS and MIM3 Sequence Primers design (mutant MIM3_MIM2 plus N448A; N451A) 0188 Mutants MIM1; MIM2 DNA Artificial GTTTTGATTCAGCCATTACCGCCCTTGGCGCTACGGTAACCGCTCTGG and MIM3 Sequence Forward Primer 448-51 0189 Mutants MIM1; MIM2 DNA Artificial CCAGAGCGGTTACCGTAGCGCCAAGGGCGGTAATGGCTGAATCAAAAC and MIM3 Sequence Reverse Primer 448-51 0190 Mutant ME42 DNA Artificial CAACAGCGCGAAAGCCGATGCGGGAGGCCAGGCGATTGC Forward Primer ME42 Sequence 0191 Mutant ME42 DNA Artificial GCAATCGCCTGGCCTCCCGCATCGGCTTTCGCGCTGTTG Reverse Primer ME42 Sequence 0192 Mutant ME42 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Sequence of ME42 Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGCCGATGCG construct GGAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT

GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0193 Mutant ME42 PRT Artificial MSGLRINSAKADAGGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant ME42 Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0194 Mutant ME110 DNA Artificial GTCTGTTCAGGCCACTGCCGGGGCTAACTCTGATTCCGATCTG Forward Primer ME100 Sequence 0195 Mutant ME110 DNA Artificial CAGATCGGAATCAGAGTTAGCCCCGGCAGTGGCCTGAACAGAC Reverse Primer ME100 Sequence 0196 Mutant ME110 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Sequence of ME100 Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG construct GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTGCCGGGGCTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0197 Mutant ME110 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant ME110 Sequence ATAGANSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0198 Mutant ME100/110 DNA Artificial CTGATTCCGATCTGAAAGCTATCCAGGCTGAAATTCAGCAACGTC Forward Primer ME110 Sequence 0199 Mutant ME100/110 DNA Artificial GACGTTGCTGAATTTCAGCCTGGATAGCTTTCAGATCGGAATCAG Reverse Primer ME110 Sequence 0200 Mutant ME100/110 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Sequence of ME100/110 Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG construct GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTGCCGGGGCTAACTCTGATTCCG ATCTGAAAGCTATCCAGGCTGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0201 Mutant ME104N DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC Intermediate Mutant Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTA ME100/110 TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTGCCGGGGCTAACTCTGATTCCGATCTGAAAGCTATCCAGGCTGA AATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATCAGACTCAATTTAACGGTGTTAAA GTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTAC CATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCC GGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGG TAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTA ATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAG GTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGT TAA 0202 Mutant ME100/110 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant ME110/110 Sequence ATAGANSDSDLKAIQAEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0203 Mutant ME104 DNA Artificial GCCACTAACGGGACTAACGCTGATGCCGCTCTGAAATCTATCCAG Forward Primer ME104 Sequence 0204 Mutant ME104 DNA Artificial CTGGATAGATTTCAGAGCGGCATCAGCGTTAGTCCCGTTAGTGGC Reverse Primer ME104 Sequence 0205 Mutant ME104 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Sequence of ME104 Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG construct GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACGCTGATGCCG CTCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0206 Mutant ME104 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant ME104 Sequence ATNGTNADAALKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0207 Mutant ME104N DNA Artificial GCCACTGCCGGGGCTAACGCTGATGCCGCTCTGAAAGCTATCCAG Primer FME104New Sequence 0208 Mutant ME104N DNA Artificial CTGGATAGCTTTCAGAGCGGCATCAGCGTTAGCCCCGGCAGTGGC Primer RME104New Sequence 0209 Mutant ME104N DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Sequence of construct Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG ME104New GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTGCCGGGGCTAACGCTGATGCC GCTCTGAAAGCTATCCAGGCTGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAAT CAGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGT GCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTT GATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCA TTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCC ATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0210 Mutant ME104N PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant ME104N Sequence ATAGANADAALKAIQAEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0211 Mutant ME110 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Sequence of ME110 Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG construct GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAAGCTATCCAGGCTGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0212 Mutant ME110 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant ME110 Sequence ATNGTNSDSDLKAIQAEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0213 Mutant ME117 DNA Artificial CTATCCAGGATGAAATTCAGGCACGTCTGGCAGAAATCGATCGCG Forward Primer ME117 Sequence 0214 Mutant ME117 DNA Artificial CGCGATCGATTTCTGCCAGACGTGCCTGAATTTCATCCTGGATAG Reverse Primer ME117 Sequence 0215 Mutant ME117 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Sequence of 33ML Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG construct GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG (should this say TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA ME117?) CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGGCACGTCTGGCAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0216 Mutant ME117 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant ME117 Sequence ATNGTNSDSDLKSIQDEIQARLAEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0217 Mutant ME124 DNA Artificial GGAAGAAATCGATGCCGTTTCTGCTGCGACTCAATTTAACGGTGTTAAAGTCCTGTCTC Forward Primer ME104 Sequence 0218 Mutant ME124 DNA Artificial GAGACAGGACTTTAACACCGTTAAATTGAGTCGCAGCAGAAACGGCATCGATTTCTTCC Reverse Primer ME104 Sequence 0219 Mutant ME124 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Sequence of ME124 Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG construct GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATGCCGTTTCTGCTG CGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0220 Mutant ME124 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant ME124 Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDAVSAATQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG

0221 Mutant ME124P DNA Artificial CAGCAACGTCTGGAAGAAATCGATGCCGTTTCTAATCAGACTCAATTTAACGG Forward Primer ME124P Sequence 0222 Mutant ME124P DNA Artificial CCGTTAAATTGAGTCTGATTAGAAACGGCATCGATTTCTTCCAGACGTTGCTG Reverse Primer ME124P Sequence 0223 Mutant ME124 DNA Artificial ATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCGGCAGGCCAGGCGATTGCTAACC Expressed Mutant Sequence GCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCGTAACGCTAACGACGGCATTTCTA ME124P TTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAACAACCTGCAGCGTGTGCGTGAG TTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCGATCTGAAATCTATCCAGGATGAA ATTCAGCAACGTCTGGAAGAAATCGATGCCGTTTCTAATCAGACTCAATTTAACGGTGTTAAA GTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTGCTAACGATGGTGAAACCATTAC CATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTGATGGGTTCAATGTTAATTCCCC GGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCATTGTCAAAAGTGGACGCAGTTC GTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCATTACCAACCTTGGCAATACGG TAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCTGACTATGCAACGGAAGTTTCTA ATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCCGTTCTGGCGCAGGCTAACCAG GTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTCTCATCATCATCATCATCATGGT TAA 0224 Mutant ME124P DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT ME124P Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATGCCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0225 Mutant ME124P PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ ME124P Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDAVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0226 Mutant ME132 DNA Artificial CGTTTCTAATCAGACTCAATTTGCCGCTGTTAAAGTCCTGTCTCAGGACAACC Forward Primer ME132 Sequence 0227 Mutant ME132 DNA Artificial GGTTGTCCTGAGACAGGACTTTAACAGCGGCAAATTGAGTCTGATTAGAAACG Reverse Primer ME132 Sequence 0228 Mutant ME132 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Sequence of ME132 Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG construct GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTGCCGCTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0229 Mutant ME132 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant ME117 Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFAAVKVLSQDNQMKIQVGANDGETITIDLQKIDV (ME132?) KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0230 Mutant ME142 DNA Artificial GTTAAAGTCCTGTCTCAGGACAACGCGATGGCAATCCAGGTTGGTGCTAACG Forward Primer ME142 Sequence 0231 Mutant ME142 DNA Artificial CGTTAGCACCAACCTGGATTGCCATCGCGTTGTCCTGAGACAGGACTTTAAC Reverse Primer ME142 Sequence 0232 Mutant ME142 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Sequence of ME142 Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG construct GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACGCGATGGCAATCCAGGTTGGT GCTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTT GATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCA TTGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCC ATTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0233 Mutant ME142 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant ME142 Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNAMAIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0234 Mutant ME150 DNA Artificial GATGAAAATCCAGGTTGGTGCTAGCGCTGCTGAAACCATTACCATCGATCTGC Forward Primer ME150 Sequence 0235 Mutant ME150 DNA Artificial GCAGATCGATGGTAATGGTTTCAGCAGCGCTAGCACCAACCTGGATTTTCATC Reverse Primer ME150 Sequence 0236 Mutant ME150 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Sequence of ME150 Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG construct GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAGCGCTGCTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACTATGCAACGGAAGTTTCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTCC GTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTTC TCATCATCATCATCATCATGGTTAAGTCGAC 0237 Mutant ME150 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant ME150 Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGASAAETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADYATEVSNMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0238 Mutant ME468 DNA Artificial GCCGTATCGAAGATGCTGACGCTGGAGCGGAAGTTGCTAATATGTCTAAAGCGCAG Forward Primer ME468 Sequence 0239 Mutant ME468 DNA Artificial CTGCGCTTTAGACATATTAGCAACTTCCGCTCCAGCGTCAGCATCTTCGATACGGC everse Primer ME468 Sequence 0240 Mutant ME468 DNA Artificial TAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCCCCTCTAGAATAATTTTGTTT Sequence of ME468 Sequence AACTTTAAGAAGGAGATATACATATGAGCGGGTTACGGATCAACAGCGCGAAAGACGATGCG construct GCAGGCCAGGCGATTGCTAACCGCTTCACTTCTAATATCAAAGGTCTGACTCAGGCTTCCCG TAACGCTAACGACGGCATTTCTATTGCGCAGACCACTGAAGGTGCGCTGAATGAAATCAACAA CAACCTGCAGCGTGTGCGTGAGTTGTCTGTTCAGGCCACTAACGGGACTAACTCTGATTCCG ATCTGAAATCTATCCAGGATGAAATTCAGCAACGTCTGGAAGAAATCGATCGCGTTTCTAATC AGACTCAATTTAACGGTGTTAAAGTCCTGTCTCAGGACAACCAGATGAAAATCCAGGTTGGTG CTAACGATGGTGAAACCATTACCATCGATCTGCAAAAAATTGATGTGAAAAGCCTTGGCCTTG ATGGGTTCAATGTTAATTCCCCGGGAAGTACCGCTAACCCACTGGCTTCAATTGATTCTGCAT TGTCAAAAGTGGACGCAGTTCGTTCTTCTCTGGGGGCAATTCAAAACCGCTTTGATTCAGCCA TTACCAACCTTGGCAATACGGTAACCAATCTGAACTCCGCGCGTAGCCGTATCGAAGATGCT GACGCTGGAGCGGAAGTTGCTAATATGTCTAAAGCGCAGATTCTGCAGCAGGCTGGTACTTC CGTTCTGGCGCAGGCTAACCAGGTTCCGCAAAACGTCCTCTCTTTACTGGTTCCGCGGGGTT CTCATCATCATCATCATCATGGTTAAGTCGAC 0241 Mutant ME468 PRT Artificial MSGLRINSAKDDAAGQAIANRFTSNIKGLTQASRNANDGISIAQTTEGALNEINNNLQRVRELSVQ Mutant ME468 Sequence ATNGTNSDSDLKSIQDEIQQRLEEIDRVSNQTQFNGVKVLSQDNQMKIQVGANDGETITIDLQKIDV KSLGLDGFNVNSPGSTANPLASIDSALSKVDAVRSSLGAIQNRFDSAITNLGNTVTNLNSARSRIED ADAGAEVANMSKAQILQQAGTSVLAQANQVPQNVLSLLVPRGSHHHHHHG 0242 Linker PRT Artificial SPG Sequence 0243 Lru283 PRT Artificial mghhhhhhsgMEEFNMRINTNVAAMNTYSRLTAANTAKSNSLAKLSSGLRINKAGDDAAGLAISEKM Sequence KSQIGGLTQAKRNAQDGISLVQTAEGALNETHSILERMRDLAVQGSNGTLTSSDRGSINKELKALH QELTRISNTTEFNTQKLFSQTKQKSVTFTFQIGANAGQTLSVAITAMSGEALLVSTDAKFSLNAAGT NAGAMIKSIDAAIAKVSDQRADLGAVQNRLEHTINNLTATNENLSDANSRIRDVDMAEEMMTFTKS NILSQAATSMLAQANAMPNSVLNLLQG 0244 Tpe270 PRT Artificial mghhhhhhsgMRINHNISALNAWRNIDQTQYSMSKTLERLSSGLRINRAGDDAAGLAISEKMRGQIK Sequence GLNMAIKNAQDAISLIQTAEGALTEVHSILQRMRELAVQAASDTNTNVDREQIQKEIDQLREEIDRIA RTTEFNTKKLLDGKLEGFRSQVDAKVVTGGNINVQLGTVSSKAVEGTYVIEVGaAERAIMVVDAAI HRVSTARAALGAIQNRLEHTISNLGVAAENLTAAESRIRDADMAKEMMEFTKQQILLQSSMAMLAQ SNTLPQNVLQLMR 0245 Tpe159w PRT Artificial mghhhhhhsGLNMAIKNAQDAISLIQTAEGALTEVHSILQRMRELAVQAASDTNTNVDREQIQKEIDQ Sequence LREEIDRIARTTEFNTKKLLDGKLEGFRSQVDAKVVTGGNINVQLGTVSSKAVEGTYVIEVGaAERA IMVVDAAIHRVSTARAALGAIQNRLEHTISNLG 0246 Chy275 PRT Artificial mghhhhhhsgMSLRINNNIEALNAWRALNSTSNALQKSMEKLSSGLRINRAGDDAAGLAISEKLRAQI Sequence RGLNQAIRNAQDGISLIQTAEGGLSEIQNILQRMRELGVQAANGTLNNQDISAITTELNQLFNEIDRI AGATEFNTKNLLAVSTGLVVTLQVGANAGQVIAFTIDNAGTASLGLSSADLAINDNASASAFISKVD SALQKVSTYRANLGSIQNRLEHTIANLGIASENLSASESRIRDVDMAAEMMNFTKNQILQQAGVAIL AQANQAPQAVLQLLR 0247 Chy162w PRT Artificial mghhhhhhsGLNQAIRNAQDGISLIQTAEGGLSEIQNILQRMRELGVQAANGTLNNQDISAITTELNQ Sequence LFNEIDRIAGATEFNTKNLLAVSTGLVVTLQVGANAGQVIAFTIDNAGTASLGLSSADLAINDNASAS AFISKVDSALQKVSTYRANLGSIQNRLEHTIANLG 0248 ChyU137 PRT Artificial mghhhhhhsGLNQAIRNAQDGISLIQTAEGGLSEIQNILQRMRELGVQAANGTLNNQDISAITTELNQ Sequence LFNEIDRIAGATEFNTKNLLAAGTASLGLSSADLAINDNASASAFISKVDSALQKVSTYRANLGSIQN RLEHTIANLG 0249 ChyN108 PRT Artificial mghhhhhhSASAFISKVDSALQKVSTYRANLGSIQNRLEHTIANLGpdGLNQAIRNAQDGISLIQTAEG Sequence GLSEIQNILQRMRELGVQAANGTLNNQDISAITTELNQLFNEIDRIA 0250 ChyZ94 PRT Artificial mghhhhhhsNNQDISAITTELNQLFNEIDRIAGATgsGGLSEIQNILQRMRELGVQAANGTLNggSASA Sequence FISKVDSALQKVSTYRANLGSIQNRLEHTIANLG 0251 Fir161B PRT Artificial mghhhhhhsGLAQASRNAQDAISIAQTAEGALDETQSILQRVRELGVQGANGTLTADDINALQAEVD Sequence QLIAEIDRIAGATEFNTQNLLDGSFTTKAFQVGANSGQNMTLTIGKMDTTTLGLSSADLAINDNAFA NGAISTVDSALQKVSAERAKLGAIQNRLEHTIANLG 0252 Fir161MNB PRT Artificial mghhhhhhsGLAQASRQAQDAISIAQTAEGALDETQSILQRVRELGVQGADGTLTADDIDALQAEVD Sequence QLIAEIDRIAGATEFATQKLLDGSFTTKAFQVGAASGQDVTLTIGKVDTTTLGLSSADLAIDSAAFAD GAISTVDSALQKVSAERAKLGAIQNRLEHTIAQLG

[0054] In some embodiments, the aluminum gel or salt is selected from aluminum hydroxide, aluminum phosphate, and potassium aluminum sulfate, AS04 (which is composed of aluminum salt and MPL), and ALHYDROGEL. In some embodiments, the aluminum gel or salt is a formulation or mixture with any of the additional adjuvants described herein.

[0055] In some embodiments, adjuvants in addition to the described flagellin-based agent and an aluminum gel or salt find use in the present invention. In some embodiments, the additional adjuvant is selected from, oil-in-water emulsion formulations, saponin adjuvants, ovalbumin, Freunds Adjuvant, cytokines, and chitosans. Illustrative additional adjuvants include, but are not limited to: (1) ovalbumin (e.g. ENDOFIT), which is often used for biochemical studies; (2) oil-in-water emulsion formulations (with or without other specific immunostimulating agents such as muramyl peptides or bacterial cell wall components), such as for example (a) MF59 (PCT Publ. No. WO 90/14837), containing 5% Squalene, 0.5% Tween 80, and 0.5% Span 85 (optionally containing various amounts of MTP-PE) formulated into submicron particles using a microfluidizer such as, for example, Model HOy microfluidizer (Microfluidics, Newton, Mass.), (b) SAF, containing 10% Squalane, 0.4% Tween 80, 5% pluronic-blocked polymer L121, and thr-MDP either microfluidized into a submicron emulsion or vortexed to generate a larger particle size emulsion, (c) RIBI adjuvant system (RAS), (RIBI IMMUNOCHEM, Hamilton, Mo.) containing 2% Squalene, 0.2% Tween 80, and, optionally, one or more bacterial cell wall components from the group of monophosphorylipid A (MPL), trehalose dimycolate (TDM), and cell wall skeleton (CWS), including MPL+CWS (DETOX.TM.); and (d) ADDAVAX (Invitrogen); (3) saponin adjuvants, such as STIMULON (Cambridge Bioscience, Worcester, Mass.) may be used or particles generated therefrom such as ISCOMs (immunostimulating complexes); (4) Complete Freunds Adjuvant (CFA) and Incomplete Freunds Adjuvant (IFA); (5) cytokines, such as interleukins (by way of non-limiting example, IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-12, etc.), interferons (e.g., gamma interferon), macrophage colony stimulating factor (M-CSF), tumor necrosis factor (TNF), etc; (6) chitosans and other derivatives of chitin or poly-N-acetyl-D-glucosamine in which the greater proportion of the N-acetyl groups have been removed through hydrolysis (see, e.g., European Patent Application 460 020, which is hereby incorporated by reference in its entirety, disclosing pharmaceutical formulations including chitosans as mucosal absorption enhancers; and (7) other substances that act as immunostimulating agents to enhance the effectiveness of the composition, e.g., monophosphoryl lipid A. In other embodiments, the additional adjuvant is one or more of a flagellin-based agent (e.g. CBLB502 or any of the agents of Table 1), an aluminium salt or gel, a pattern recognition receptors (PRR) agonist, CpG ODNs and imidazoquinolines. In some embodiments, the additional adjuvant is one or more of cyclic [G(3',5')pA(3',5')p] (e.g. 3'3'-cGAMP VACCIGRADE); cyclic [G(2',5')pA(3',5')p]2'3' (e.g. 2'3' cGAMP VACCIGRADE); cyclic [G(2',5')pA(2',5')p] (e.g. 2'2'-cGAMP VACCIGRADE), cyclic diadenylate monophosphate (e.g. c-di-AMP VACCIGRADE); cyclic diguanylate monophosphate (e.g. c-di-GMP VACCIGRADE); TLR7 agonist-imidazoquinolines compound (e.g. TLR7 agonists, such as, for example, Gardiquimod VACCIGRADE, Imiquimod VACCIGRADE, R848 VACCIGRADE); lipopolysaccharides (e.g. TLR4 agonists), such as that from E. coli 0111:B4 strain (e.g. LPS-EB VACCIGRADE); monophosphoryl lipid A (e.g. MPLA-SM VACCIGRADE and MPLA Synthetic VACCIGRADE); N-glycolylated muramyldipeptide (e.g. N-Glycolyl-MDP VACCIGRADE); CpG ODN, class A and/oror CpG ODN, class B and/or CpG ODN, class C (e.g. ODN 1585 VACCIGRADE, ODN 1826 VACCIGRADE, ODN 2006 VACCIGRADE, ODN 2395 VACCIGRADE), a triacylated lipoprotein (e.g. Pam3CSK4 VACCIGRADE); Polyinosine-polycytidylic acid (e.g. Poly(I:C) (HMW) VACCIGRADE); and cord factor (i.e. mycobacterial cell wall component trehalose 6,6' dimycolate (TDM,)) or an analog thereof (e.g. TDB VACCIGRADE, TDB-HS15 VACCIGRADE). In some emobodiments, the additional adjuvant is a TLR agonist (e.g. TLR1, and/or TLR2, and/or TLR3, and/or TLR4, and/or TLR5, and/or TLR6, and/or TLR7, and/or TLR8, and/or TLR9, and/or TLR10, and/or TLR11, and/or TLR12, and/or TLR13), a nucleotide-binding oligomerization domain (NOD) agonist, a stimulator of interferon genes (STING) ligand, or related agent.

[0056] In some embodiments, the additional adjuvants is one or more of a mineral adjuvant, gel-based adjuvant, tensoactive agent, bacterial product, oil emulsion, particulated adjuvant, fusion protein, and lipopeptide. Other mineral salt adjuvants, besides the aluminum adjuvants described elsewhere, include salts of calcium (e.g. calcium phosphate), iron and zirconium. Other gel-based adjuvants, besides the aluminum gel-based adjuvants described elsewhere, include Acemannan. Tensoactive agents include Quil A, saponin derived from an aqueous extract from the bark of Quillaja saponaria; saponins, tensoactive glycosides containing a hydrophobic nucleus of triterpenoid structure with carbohydrate chains linked to the nucleus, and QS-21. Bacterial products include cell wall peptidoglycan or lipopolysaccharide of Gram-negative bacteria (e.g. from Mycobacterium spp., Corynebacterium parvum, C. granulosum, Bordetella pertussis and Neisseria meningitidis), N-acetyl muramyl-L-alanyl-D-isoglutamine (MDP), different compounds derived from MDP (e.g. threonyl-MDP), lipopolysaccharides (LPS) (e.g. from the cell wall of Gram-negative bacteria), trehalose dimycolate (TDM), and DNA containing CpG motifs. Oil emulsions include FIA, Montanide, Adjuvant 65, Lipovant, the montanide family of oil-based adjuvants, and various liposomes. Among particulated and polymeric systems, poly (DL-lactide-coglycolide) microspheres have been extensively studied and find use herein.

[0057] Further, in some embodiments, cytokines are an adjuvant of the present invention (e.g. IFN-.gamma. and granulocyte-macrophage colony stimulating factor (GM-CSF)). Also carbohydrate adjuvants (e.g. inulin-derived adjuvants, such as, gamma inulin, algammulin (a combination of .gamma.-inulin and aluminum hydroxide), and polysaccharides based on glucose and mannose, such as glucans, dextrans, lentinans, glucomannans and galactomannans) find use in the present invention. In some embodiments, adjuvant formulations are useful in the present invention and include alum salts in combination with other adjuvants such as Lipid A, algammulin, immunostimulatory complexes (ISCOMS), which are virus like particles of 30-40 nm and dodecahedric structure, composed of Quil A, lipids, and cholesterol.

[0058] In some embodiments, the additional adjuvants are described in Jennings et al. Adjuvants and Delivery Systems for Viral Vaccines-Mechanisms and Potential. In: Brown F, Haaheim LR, (eds). Modulation of the Immune Response to Vaccine Antigens. Dev. Biol. Stand, Vol. 92. Basel: Karger 1998; 19-28 and/or Sayers et al. J Biomed Biotechnol. 2012; 2012: 831486, and/or Petrovsky and Aguilar, Immunology and Cell Biology (2004) 82, 488-496 the contents of which are hereby incorporated by reference in their entireties.

[0059] In various embodiments, the present adjuvants (e.g. flagellin-based agent and an aluminum gel or salt) may be part of live and attenuated, or killed or inactivated, or toxoid, or subunit or conjugate vaccines.

[0060] In various embodiments, the present adjuvants (e.g. flagellin-based agent and an aluminum gel or salt) may be part of one or more approved vaccines and/or the antigens of one or more approved vaccines may be the antigens of the present invention. In some embodiments, the approved vaccines include: Adenovirus; Anthrax (Biothrax); BCG (Tice); DT (Sanofi); DTaP (Daptacel); DTaP (Infanrix); DTaP-HepB-IPV (Pediarix); DTaP-IPV (Kinrix); DTaP-IPV/Hib (Pentacel); Hib (ActHIB); Hib (Hiberix); Hib (PedvaxHlB); Hib/Hep B (Comvax); Hib/Mening. CY (MenHibrix); Hep A (Havrix); Hep A (Havrix); Hep B (Engerix-B); Hep B (Recombivax); Hep A/Hep B (Twinrix); Human Papillomavirus (HPV) (Cerverix); Human Papillomavirus (HPV) (Gardasil); Influenza (Afluria); Influenza (Agriflu); Influenza (Fluarix); Influenza (Flublok); Influenza (Flucelvax); Influenza (Fluvirin); Influenza (Flulevel); Influenza (Fluzone: Standard, High-Dose, & Intradermal); Influenza (FluMist); Japanese Encephalitis (Ixiaro); Meningococcal (MCV4-Menactra); Meningococcal (MCV4-Menveo); Meningococcal (MPSV4-Menomune); MMR (MMR-II); MMRV (ProQuad); Pneumococcal (PCV13--Prevnar 13); Pneumococcal (PPSV-23--Pneumovax); Polio (IPV--Ipol); Rabies (Imovax); Rabies (RabAvert); Rotavirus (RotaTeq); Rotavirus (Rotarix); Smallpox (Vaccinia--ACAM2000); Td (Decavac); Td (Tenivac); Td (Mass Biologics); Tdap (Adacel); Tdap (Boostrix); Typhoid (inactivated--Typhim Vi); Typhoid (oral--Ty21a); Varicella (Varivax); Yellow Fever (YF-Vax); and Zoster (Shingles--Zostavax).

[0061] In various embodiments, the present adjuvants (e.g. flagellin-based agent and an aluminum gel or salt) may be part of one or more illustrative vaccines and/or the antigens of one or more illustrative vaccines may be the antigens of the present invention. Illustrative vaccines include, by way of example, subunit vaccine and inactivated or "killed" vaccine (e.g. Infanrix-IPV/Hib (Bordetella pertussis), Infanrix-IPV/Hib (Haemophilus influenzae), Infanrix-IPV/Hib (Poliovirus), Infanrix-IPV/Hib (Clostridium tetani), Infanrix-IPV/Hib (Corynebacterium diphtheriae), Infanrix-hexa (Bordetella pertussis), Infanrix-hexa (Haemophilus influenzae), Infanrix-hexa (Poliovirus), Infanrix-hexa (Hepatitis B virus), Infanrix-hexa (Clostridium tetani), Infanrix-hexa (Corynebacterium diphtheriae), Infanrix-IPV (Bordetella pertussis), Infanrix-IPV (Poliovirus), Infanrix-IPV (Clostridium tetani), Infanrix-IPV (Corynebacterium diphtheriae), Infanrix/Hib (Corynebacterium diphtheriae), Pediarix (Clostridium tetani), Pediarix (Poliovirus), Pediarix (Hepatitis B virus), ViVaxim (Salmonella spp.), ViVaxim (Hepatitis A virus); subunit vaccines (e.g. 5CVMB (Neisseria meningitidis), B. pertussis CyaA protein vaccine (Bordetella pertussis), B. pertussis PTx protein vaccine (Bordetella pertussis), Cancer VEGFA protein vaccine (Cancer), E. coli vaccine using intimin polypeptide (Escherichia coli), Engerix-B (Hepatitis B virus), H. pylori VacA protein vaccine (Helicobacter pylori), HC of type C and D (Clostridium botulinum), Infanrix/Hib (Bordetella pertussis), Infanrix/Hib (Haemophilus influenzae), Infanrix/Hib (Clostridium tetani), M. gallisepticum TM-1 Protein Subunit Vaccine (Mycoplasma gallisepticum), MDA-modified human apo B-100 peptide Vaccine (Atherosclerosis), MSP3-LSP with aluminium hydroxide (Plasmodium spp.), Mumps HN Protein Subunit Vaccine (Mumps virus), N. miningitidis TBP2 Protein Vaccine (Neisseria meningitidis), P. aeruginosa Oprl Protein Vaccine (Pseudomonas aeruginosa), P. falciparum Subunit SE36 Protein Vaccine (Plasmodium spp.), Phleum pratense Allergy Phl p 12 Subunit Vaccine (Allergy), Recombivax HB (Hepatitis B virus), S. pneumoniae ClpP protein Vaccine (Streptococcus pneumoniae); toxoid vaccine (e.g. BoNT/F(Hc) (Clostridium botulinum), DAPTACEL (Corynebacterium diphtheriae), Infanrix (Bordetella pertussis), Infanrix (Clostridium tetani), KINRIX (Clostridium tetani), PBT (Clostridium botulinum), Pediarix (Bordetella pertussis), inactivated or "killed" vaccines (e.g. Avaxim (Hepatitis A virus), Avaxim-Pediatric (Hepatitis A virus), FSME-IMMUN (Tick-borne Encephalitis Virus (TBEV)), Infanrix (Corynebacterium diphtheriae), Ixiaro (Japanese encephalitis virus), KINRIX (Corynebacterium diphtheriae), and Pediarix (Corynebacterium diphtheriae)); and conjugate vaccines (e.g., Arabinomannan-tetanus toxoid conjugate (Mycobacterium tuberculosis)), CCPS-P64kR (Neisseria meningitidis), COMVAX (Haemophilus influenzae), Menjugate (Neisseria meningitidis), Neisvac-C (Neisseria meningitidis), and PedvaxHIB (Haemophilus influenzae)).

[0062] In some embodiments, the present adjuvants (e.g. flagellin-based agent and an aluminum gel or salt) are combined in a vaccine targeting a substance abuse. For example, in one embodiment, the present adjuvants are used in vaccines against addition to fentanyl, heroin, morphine, opium, oxycodone, hydrocodone, ketamine, PCP, barbiturates, benzodiazepines, flunitrazepam, GHB, methaqualone, hashish, marijuana, LSD, mescaline, psilocybin, amphetamine, cocaine, MDMA, methamphetamine, methylphenidate, and nicotine (e.g. TA-CD (Celtic Pharma), those described in US Patent Publication No. 2013/0011432, the contents of which are hereby incorporated by reference (e.g. using 6-(2R,35)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1]octane-2-carbonyloxy-hexanoic acid (GNC) or 6-((2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido)hexanoic acid) (GNE) as the antigen, and TA-NIC (Celtic Pharma)).

[0063] In some embodiments, the present adjuvants (e.g. flagellin-based agent and an aluminum gel or salt) and/or the present vaccines may comprise any one of the adjuvants or antigens annotated in the VIOLIN or Vaxjo databases (as described in He et al. Nucleic Acids Research. 2014. 42 (D1): D1124-D1132 and Xiang et al. Nucleic Acids Res. 2008 January; 36: D923-8, the contents of which are hereby incorporated by reference in their entirety).

[0064] In various embodiments, the present adjuvants (e.g. flagellin-based agent and an aluminum gel or salt) may be part of one or more cancer vaccines and/or the antigens of one or more cancer vaccines may be the antigens of the present invention. Illustrative cancer vaccines include therapeutic and preventative vaccines. For instance, cancer vaccines include ONCOPHAGE (ANTIGENICS INC., approved in Russia in 2008 for kidney cancer), APC8015/Sipuleucel-T/PROVENGE (DENDREON, for, e.g. metastatic hormone-refractory prostate cancer), CANCERVAX (CANVAXIN), GENITOPE CORP (MYVAX personalized immunotherapy), and FAVRILLE INC (FAVID), preventive vaccines which attack the cancer-causing viruses human papillomavirus (e.g. CERVARIX (GSK) and GARDASIL (MERCK)), hepatitis A virus (e.g. CERVARIX (GSK) and GARDASIL (MERCK)), and hepatitis B virus (e.g. RECOMBIVAX HB (MERCK), ENGERIX-B (GSK), ELOVAC B (HUMAN BIOLOGICALS INSTITUTE), GENEVAC B (SERUM INSTITUTE), SHANVAC B, etc.

[0065] In various embodiments, the present adjuvants (e.g. flagellin-based agent and an aluminum gel or salt) may be part of one or more allergen vaccines and/or the antigens of one or more allergen vaccines may be the antigens of the present invention. For instance, subcutaneous immunotherapy (SCIT) allergen compositions and methods are applicable to the present invention (e.g. "allergy shots"). For example, vaccinations for allergic rhinitis and conjunctivitis (e.g. pollen (including ragweed), dust mites, animal dander and airborne mold spores); allergic or extrinsic bronchial asthma (e.g. house dust mites, pollen, animal dander, mold (Cladosporium), latex); and insect venom hypersensitivity. Allergens include pollen (e.g. tree, grass, weed), pet dander (e.g. cat pelt), dust mites, airborne molds, occupational aeroallergens, honey bee venom, yellow jacket venom, hornet venom, wasp venom, and fire ant venom.

[0066] In various embodiments, the antigens of the present vaccines may be the antigens of live and attenuated or killed or inactivated or toxoid or a subunit or conjugate vaccines. In various embodiments, the antigen of the present vaccines is an antigen of any of the vaccines described herein. For example, in some embodiments, the present antigen is that of one or more of the following vaccines: DTP (diphtheria-tetanus-pertussis vaccine), DTaP (diphtheria-tetanus-acellular pertussis vaccine), Hib (Haemophilus influenzae type b) conjugate vaccines, Pneumococcal conjugate vaccine, Hepatitis A vaccines, Poliomyelitis vaccines, Yellow fever vaccines, Hepatitis B vaccines, combination DTaP, Tdap, Hib, Human Papillomavirus (HPV) vaccine, Anthrax vaccine, Bacillus Calmette-Guerin (Tb), and Rabies vaccine.

[0067] In various embodiments, the flagellin-based agent and antigen are adsorbed to the aluminum gel or salt. In some embodiments, the flagellin-based agent and aluminum gel or salt are mixed to form a stable complex. In some embodiments, the flagellin-based agent and aluminum gel or salt are mixed in a ratio that is substantially below a loading capacity of the aluminum salt. In some embodiments, the flagellin-based agent and aluminum gel or salt are present in a ratio that is substantially below a loading capacity of the aluminum salt. In various embodiments, the flagellin-based agent and aluminum gel or salt are mixed or present in a ratio (w/w) of about 1:500, or about 1:600, or about 1:700, or about 1:800, or about 1:900, or about 1:1000, or about 1:2000, or about 1:5000, or about 1:6000, or about 1:7000, or about 1:8000, or about 1:9000, or about 1:10000. In some embodiments, the flagellin-based agent and aluminum gel or salt are mixed in a ratio (w/w) of about 1:500 or less. In some embodiments, the flagellin-based agent and aluminum gel or salt are present in a ratio that is substantially below a loading capacity of the aluminum salt even in the presence of anitigen.

[0068] The loading (or adsorption) capacity of the adjuvant (e.g. the aluminum gel or salt) can be measured using a variety of analytical methods. In general, it is done by comparing the protein content in the aqueous phase of the agent being loaded or adsorbed (e.g. flagellin-based agent and/or antigen solution) before and after adsorption onto the adjuvant. For instance, the Ramon flocculation test may be used (as is used to determine the adsorption of diphtheria and tetanus toxoid). Further, loading can be measured using immunoprecipitation techniques (e.g. quantitative immunoelectrophoresis or single radial immunodiffusion) or spectrophotometric techniques (e.g. the BCA method) ELISA methods may also be used as can immunoelectrophoresis or HPLC. The aluminum content in the final vaccine can be monitored using a number of known techniques, including spectrometric methods, such as for example atomic adsorption spectrometry.

[0069] In some embodiments, the amount of aluminum gel or salt in the vaccines and/or adjuvants described herein is about 0.05 to about 1.0 mg/dose, or about 0.125 to about 0.625 mg/dose. In some embodiments, the amount of aluminum gel or salt in the vaccines and/or adjuvants described herein is about 0.05, or about 0.10, or about 0.15, or about 0.20, or about 0.25, or about 0.30, or about 0.35, or about 0.40, or about 0.45, or about 0.50, or about 0.55, or about 0.60, or about 0.65, or about 0.70, or about 0.75, or about 0.80, or about 0.85, or about 0.90, or about 0.95, or about 1.0 mg/dose.

[0070] In some embodiments, the amount of flagellin-based agent is about 0.03 to about 5 .mu.g/dose (e.g. about 0.03 .mu.g/dose, about 0.1 .mu.g/dose, about 0.3 .mu.g/dose, about 0.5 .mu.g/dose about 1.0 .mu.g/dose, about 1.5 .mu.g/dose, about 2.0 .mu.g/dose, about 2.5 .mu.g/dose, about 3.0 .mu.g/dose, about 4.0 .mu.g/dose, about 4.5 .mu.g/dose, about 5.0 .mu.g/dose). In various embodiments, the present compositions and methods comprise doses of flagellin-based agent that are less than about 5 .mu.g/dose, or less than 4 .mu.g/dose, or less than 3 .mu.g/dose, or less than 2 .mu.g/dose, or less than 1 .mu.g/dose, or less than 0.5 .mu.g/dose. In some embodiments, the present compositions and methods comprise low doses of flagellin-based agent.

[0071] In various embodiments, the present compositions and methods do not involve covalently attaching an antigen to the flagellin-based agent either as a fusion protein or via chemical conjugation. In various embodiments, the present compositions do not have either equimolar ratio of antigen to flagellin-based agent (as in a fusion) or several molecules of hapten per one molecule of flagellin-based agent (as in chemical conjugates). In various embodiments, the amount of flagellin-based agent in any of the present vaccines is less than the amount of antigen. In various embodiments, the amount of flagellin-based agent in any of the present vaccines is less than the amount of antigen. In various embodiments, the amount of flagellin-based agent in any of the present vaccines is substantially less than the amount of antigen. In various embodiments, the amount of flagellin-based agent in any of the present vaccines is about 500-fold, or about 450-fold, or about 400-fold, or about 350-fold, or about 325-fold, or about 300-fold, or about 250-fold, or about 200-fold, or about 150-fold, or about 100-fold, or about 50-fold less than the amount of antigen.

[0072] In various embodiments, the combination of flagellin-based agent and alum do not substatially effect TLR5 interaction by the flagellin-based agent.

[0073] In various embodiments, the present compositions and methods do not induce production of TNF.alpha..

[0074] In various embodiments the present combination of flagellin-based agent and alum is subtantially stable at low temperatures for about one week (e.g. at about 4.degree. C. for about 3 days, or about 5 days, or about 6 days, or about 7 days, or about 10 days).

[0075] In another aspect, the present invention relates to a method of vaccinating a subject against a disorder, comprising administering an effective amount of a vaccine comprising an adjuvant comprising a flagellin-based agent and an aluminum gel or salt and an antigen associated with the disorder. In another aspect, the invention relates to a use of vaccine comprising an adjuvant comprising a flagellin-based agent and an aluminum gel or salt and an antigen associated with a disorder for vaccinating a subject against the disorder. In another aspect, the invention relates to a use of an effective amount of vaccine comprising an adjuvant comprising a flagellin-based agent and an aluminum gel or salt and an antigen associated with a disorder in the manufacture of a medicament for vaccinating a subject against the disorder.

[0076] In another aspect, the present invention relates to a method of immunostimulating a subject in advance of or concurrent with vaccination, comprising administering an effective amount of an adjuvant comprising a flagellin-based agent and an aluminum gel or salt, wherein both T.sub.H1 and T.sub.H2-mediated immune responses are immunostimulated. In another aspect, the invention relates to a use of an effective amount of an adjuvant comprising a flagellin-based agent and an aluminum gel or salt for immunostimulating a subject in advance of or concurrent with vaccination. In another aspect, the invention relates to a use of an effective amount of an adjuvant comprising a flagellin-based agent and an aluminum gel or salt in the manufacture of a medicament for immunostimulating a subject in advance of or concurrent with vaccination.

[0077] In various embodiments, the vaccine described herein causes an improvement in adjuvant properties relative to a vaccine comprising the antigen and the aluminum gel or salt alone (or flagellin-based agent and antigen alone). In various embodiments, the vaccine and/or adjuvant described herein causes a broader, more diverse, more robust and longer lasting immunostimulatory effect than the vaccine comprising the antigen and the aluminum gel or salt alone (or flagellin-based agent and antigen alone) and/or the adjuvant comprising the aluminum gel or salt alone (or the adjuvant comprising the flagellin-based agent alone).

[0078] In some embodiments, the described vaccine and/or described adjuvant causes an increase in titer of 1 or more of, or 2 or more of, or 3 or more of, or all of IgG1, IgG2a, IgG2b, and IgG3 antibodies (e.g. relative to the adjuvant comprising the aluminum gel or salt or flagellin-based agent alone, or relative to the vaccine comprising the antigen and the aluminum gel or salt alone or flagellin-based agent alone)). In some embodiments, the described vaccine and/or described adjuvant causes a relative increase in the titer of all of IgG1, IgG2a, IgG2b, and IgG3 antibodies. In some embodiments, the described vaccine and/or described adjuvant causes a relative increase in the titer of more IgG3 antibodies than the described vaccine and/or described adjuvant in the absence of a flagellin-based agent (or the described vaccine and/or described adjuvant in the absence of an aluminum gel or salt alone).

[0079] In some embodiments, the antigen is administered simultaneously with or sequentially to the adjuvant.

[0080] In some embodiments, the disorder is selected from infectious diseases, cancer, allergy, and autoimmune diseases.

[0081] In some embodiments, the disorder is selected from diphtheria, tetanus, pertussis, influenza, pneumonia, hepatitis A, hepatitis B, polio, yellow fever, Human Papillomavirus (HPV) infection, anthrax, rabies, Japanese Encephalitis, meningitis, measles, mumps, rubella, gastroenteritis, smallpox, typhoid fever, varicella (chickenpox), rotavirus, and shingles.

[0082] In some embodiments, the disorder is a cancer is selected from, but not limited to, a basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma; hepatic carcinoma; hepatoma; intra-epithelial neoplasm; kidney or renal cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g., small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cavity cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; salivary gland carcinoma; sarcoma; skin cancer; squamous cell cancer; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; cancer of the urinary system; vulval cancer; lymphoma including Hodgkin's and non-Hodgkin's lymphoma, as well as B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; as well as other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome.

[0083] In some embodiments, the disorder is an allergy, selected from, by way of non-limiting example, allergic rhinitis and conjunctivitis, allergic or extrinsic bronchial asthma, and insect venom hypersensitivity.

[0084] In some embodiments, the disorder is a substance abuse disorder (e.g. of fentanyl, heroin, morphine, opium, oxycodone, hydrocodone, ketamine, PCP, barbiturates, benzodiazepines, flunitrazepam, GHB, methaqualone, hashish, marijuana, LSD, mescaline, psilocybin, amphetamine, cocaine, MDMA, methamphetamine, methylphenidate, and nicotine).

[0085] In some embodiments, the compositions of the present invention (e.g. the described adjuvants and vaccines) can possess a sufficiently basic functional group, which can react with an inorganic or organic acid, or a carboxyl group, which can react with an inorganic or organic base, to form a pharmaceutically acceptable salt. A pharmaceutically acceptable acid addition salt is formed from a pharmaceutically acceptable acid, as is well known in the art. Such salts include the pharmaceutically acceptable salts listed in, for example, Journal of Pharmaceutical Science, 66, 2-19 (1977) and The Handbook of Pharmaceutical Salts; Properties, Selection, and Use. P. H. Stahl and C. G. Wermuth (eds.), Verlag, Zurich (Switzerland) 2002, which are hereby incorporated by reference in their entirety.

[0086] Pharmaceutically acceptable salts include, by way of non-limiting example, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, pamoate, phenylacetate, trifluoroacetate, acrylate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, isobutyrate, phenylbutyrate, a-hydroxybutyrate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, glycollate, heptanoate, hippurate, malate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, phthalate, teraphthalate, propiolate, propionate, phenylpropionate, sebacate, suberate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, naphthalene-1,5-sulfonate, xylenesulfonate, and tartarate salts.

[0087] The term "pharmaceutically acceptable salt" also refers to a salt of the compositions of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines), such as mono-; bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxyl-lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.

[0088] In some embodiments, the compositions of the present invention (e.g. the described adjuvants and vaccines) described herein are in the form of a pharmaceutically acceptable salt.

[0089] In some embodiments, the compositions of the present invention (e.g. the described adjuvants and vaccines) may comprise a pharmaceutically acceptable carrier or vehicle. Such compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration.

[0090] Pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any agent described herein is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any composition described herein, if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0091] The present invention includes the compositions of the present invention (e.g. the described adjuvants and vaccines) in various formulations. Any composition of the present invention can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule (see, e.g., U.S. Pat. No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.

[0092] Where necessary, the compositions of the present invention can also include a solubilizing agent. Also, the agents can be delivered with a suitable vehicle or delivery device as known in the art. Combination therapies outlined herein can be co-delivered in a single delivery vehicle or delivery device. Compositions for administration can optionally include a local anesthetic such as, for example, lignocaine to lessen pain at the site of the injection.

[0093] The formulations comprising the compositions of the present invention may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the therapeutic agents into association with a carrier, which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation (e.g., wet or dry granulation, powder blends, etc., followed by tableting using conventional methods known in the art).

[0094] In one embodiment, any composition of the present invention is formulated in accordance with routine procedures as a composition adapted for a mode of administration described herein.

[0095] Routes of administration include intramuscular, e.g. by injection or infusion. In some embodiments, the described adjuvant of a flagellin-based agent (e.g. CBLB502) and aluminum gel or salt may prevent systemic delivery of the flagellin-based agent and induce localized delivery. In other embodiments, routes of administration include nasal, oral, and sublingual delivery.

[0096] Routes of administration may also be intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, oral, sublingual, intranasal, transdermal, or by inhalation. In some embodiments, the administering is effected orally or by parenteral injection. The mode of administration can be left to the discretion of the practitioner, and depends in-part upon the site of the medical condition. In most instances, administration results in the release of any agent described herein into the bloodstream.

[0097] Any composition of the present invention (e.g. the described adjuvants and vaccines) can be administered orally. Such compositions can also be administered by any other convenient route, for example, by intravenous infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and can be administered together with another biologically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc., and can be used to administer.

[0098] Dosage forms suitable for parenteral administration (e.g. intravenous, intramuscular, intraperitoneal, subcutaneous and intra-articular injection and infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions (e.g. lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art.

[0099] The dosage of any composition of the present invention (e.g. the described adjuvants and vaccines) as well as the dosing schedule can depend on various parameters, including, but not limited to, the disorder being treated, the subject's general health, and the administering physician's discretion.

[0100] In vitro or in vivo assays can be employed to help identify optimal dosage ranges. For example, doses may be determined with reference Physicians' Desk Reference, 66th Edition, PDR Network; 2012 Edition (Dec. 27, 2011), the contents of which are incorporated by reference in its entirety.

[0101] For administration of a composition of the present invention (e.g. the described adjuvants and vaccines) by parenteral injection, the dosage is normally about 0.1 mg to about 250 mg per day, about 1 mg to about 20 mg per day, or about 3 mg to about 5 mg per day. Injections may be given up to four times daily. Generally, when orally or parenterally administered, the dosage of any agent described herein is normally about 0.1 mg to about 1500 mg per day, or about 0.5 mg to about 10 mg per day, or about 0.5 mg to about 5 mg per day. A dosage of up to about 3000 mg per day can be administered.

[0102] In another embodiment, delivery can be in a vesicle, in particular a liposome (see Langer, 1990, Science 249:1527-1533; Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989).

[0103] Any composition of the present invention (e.g. the described adjuvants and vaccines) can be administered by controlled-release or sustained-release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;

[0104] 5,639,476; 5,354,556; and 5,733,556, each of which is incorporated herein by reference in its entirety. Such dosage forms can be useful for providing controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the agents described herein. The invention thus provides single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.

[0105] Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, stimulation by an appropriate wavelength of light, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.

[0106] In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science 228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105).

[0107] In another embodiment, a controlled-release system can be placed in proximity of the target area to be treated, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussed in the review by Langer, 1990, Science 249:1527-1533) may be used.

[0108] Administration of a composition of the present invention (e.g. the described adjuvants and vaccines) can, independently, be once per patient or may be used in a booster strategy. Administration may be about one to about four times daily or about one to about four times per month or about one to about six times per year or once every two, three, four or five years. Administration can be for the duration of about one day or about one month, about two months, about three months, about six months, about one year, about two years, about three years, and may even be for the life of the subject. The dosage may be administered as a single dose or divided into multiple doses.

[0109] The dosage regimen utilizing any flagellin related composition (and/or additional agents) described herein can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; the pharmacogenomic makeup of the individual; and the specific compound of the invention employed. Any flagellin related composition (and/or additional agents) described herein can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily. Furthermore, any flagellin related composition (and/or additional agents) described herein can be administered continuously rather than intermittently throughout the dosage regimen.

[0110] In some embodiments, the composition of the present invention (e.g. the described adjuvants and vaccines) may be used in conjunction with one or more additional agents. In some embodiments, the invention pertains to co-administration and/or co-formulation. Any of the compositions described herein may be co-formulated and/or co-administered.

[0111] In some embodiments, any composition described herein acts synergistically when co-administered with another agent and is administered at doses that are lower than the doses commonly employed when such agents are used as monotherapy. In various embodiments, any agent referenced herein may be used in combination with any of the composition described herein.

[0112] In some embodiments, the present invention pertains to additional agents described elsewhere herein. In one embodiment, any flagellin-related agent or composition comprising the same may be used with agents that stimulate NOD receptors (e.g. NOD1 and NOD2 agonists, such as peptidoglycan, C12-iE-DAP and L18-MDP) and as described in Infect Immun. October 2013; 81(10): 3855-3864, the contents of which are hereby incorporated by reference in their entirety.

[0113] In some embodiments, the present invention pertains to chemotherapeutic agents as additional agents.

[0114] Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and CYTOXAN cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (e.g., bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (e.g., cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB 1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Intl. Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxy doxorubicin),epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as minoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; def of amine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (e.g., T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE doxetaxel (Rhone-Poulenc Rorer, Antony, France); chloranbucil; GEMZAR gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE. vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (Camptosar, CPT-11) (including the treatment regimen of irinotecan with 5-FU and leucovorin); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; combretastatin; leucovorin (LV); oxaliplatin, including the oxaliplatin treatment regimen (FOLFOX); lapatinib (Tykerb); inhibitors of PKC-.alpha., Raf, H-Ras, EGFR (e.g., erlotinib (Tarceva)) and VEGF-A that reduce cell proliferation and pharmaceutically acceptable salts, acids or derivatives of any of the above. In addition, the methods of treatment can further include the use of radiation. In addition, the methods of treatment can further include the use of photodynamic therapy.

[0115] In some embodiments, the flagellin-based agents (and/or additional agents) described herein, include derivatives that are modified, i.e., by the covalent attachment of any type of molecule to the composition such that covalent attachment does not prevent the activity of the composition. For example, but not by way of limitation, derivatives include composition that have been modified by, inter alia, glycosylation, lipidation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications can be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis of turicamycin, etc. Additionally, the derivative can contain one or more non-classical amino acids.

[0116] In still other embodiments, the flagellin-based agents (and/or additional agents) described herein further comprise a cytotoxic agent, comprising, in illustrative embodiments, a toxin, a chemotherapeutic agent, a radioisotope, and an agent that causes apoptosis or cell death. Such agents may be conjugated to a composition described herein.

[0117] The flagellin-based agents (and/or additional agents) described herein may thus be modified post-translationally to add effector moieties such as chemical linkers, detectable moieties such as for example fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties, or functional moieties such as for example streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, and radioactive materials.

[0118] Illustrative cytotoxic agents include, but are not limited to, methotrexate, aminopterin, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine; alkylating agents such as mechlorethamine, thioepa chlorambucil, melphalan, carmustine (BSNU), mitomycin C, lomustine (CCNU), 1-methylnitrosourea, cyclothosphamide, mechlorethamine, busulfan, dibromomannitol, streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP) cisplatin and carboplatin (paraplatin); anthracyclines include daunorubicin (formerly daunomycin), doxorubicin (adriamycin), detorubicin, carminomycin, idarubicin, epirubicin, mitoxantrone and bisantrene; antibiotics include dactinomycin (actinomycin D), bleomycin, calicheamicin, mithramycin, and anthramycin (AMC); and antimytotic agents such as the vinca alkaloids, vincristine and vinblastine. Other cytotoxic agents include paclitaxel (taxol), ricin, pseudomonas exotoxin, gemcitabine, cytochalasin B, gramicidin D, ethidium bromide, emetine, etoposide, tenoposide, colchicin, dihydroxy anthracin dione, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, procarbazine, hydroxyurea, asparaginase, corticosteroids, mytotane (0,P'-(DDD)), interferons, and mixtures of these cytotoxic agents.

[0119] Further cytotoxic agents include, but are not limited to, chemotherapeutic agents such as carboplatin, cisplatin, paclitaxel, gemcitabine, calicheamicin, doxorubicin, 5-fluorouracil, mitomycin C, actinomycin D, cyclophosphamide, vincristine, bleomycin, VEGF antagonists, EGFR antagonists, platins, taxols, irinotecan, 5-fluorouracil, gemcytabine, leucovorine, steroids, cyclophosphamide, melphalan, vinca alkaloids (e.g., vinblastine, vincristine, vindesine and vinorelbine), mustines, tyrosine kinase inhibitors, radiotherapy, sex hormone antagonists, selective androgen receptor modulators, selective estrogen receptor modulators, PDGF antagonists, TNF antagonists, IL-1 antagonists, interleukins (e.g. IL-12 or IL-2), IL-12R antagonists, Toxin conjugated monoclonal antibodies, tumor antigen specific monoclonal antibodies, Erbitux, Avastin, Pertuzumab, anti-CD20 antibodies, Rituxan, ocrelizumab, ofatumumab, DXL625, HERCEPTIN.RTM., or any combination thereof. Toxic enzymes from plants and bacteria such as ricin, diphtheria toxin and Pseudomonas toxin may be conjugated to the therapeutic agents (e.g. antibodies) to generate cell-type-specific-killing reagents (Youle, et al., Proc. Nat'l Acad. Sci. USA 77:5483 (1980); Gilliland, et al., Proc. Nat'l Acad. Sci. USA 77:4539 (1980); Krolick, et al., Proc. Nat'l Acad. Sci. USA 77:5419 (1980)).

[0120] Other cytotoxic agents include cytotoxic ribonucleases as described by Goldenberg in U.S. Pat. No. 6,653,104. Embodiments of the invention also relate to radioimmunoconjugates where a radionuclide that emits alpha or beta particles is stably coupled to the antibody, or binding fragments thereof, with or without the use of a complex-forming agent. Such radionuclides include beta-emitters such as Phosphorus-32, Scandium-47, Copper-67, Gallium-67, Yttrium-88, Yttrium-90, Iodine-125, Iodine-131, Samarium-153, Lutetium-177, Rhenium-186 or Rhenium-188, and alpha-emitters such as Astatine-211, Lead-212, Bismuth-212, Bismuth-213 or Actinium-225.

[0121] Illustrative detectable moieties further include, but are not limited to, horseradish peroxidase, acetylcholinesterase, alkaline phosphatase, beta-galactosidase and luciferase. Further illustrative fluorescent materials include, but are not limited to, rhodamine, fluorescein, fluorescein isothiocyanate, umbelliferone, dichlorotriazinylamine, phycoerythrin and dansyl chloride. Further illustrative chemiluminescent moieties include, but are not limited to, luminol. Further illustrative bioluminescent materials include, but are not limited to, luciferin and aequorin. Further illustrative radioactive materials include, but are not limited to, Iodine-125, Carbon-14, Sulfur-35, Tritium and Phosphorus-32.

[0122] In some embodiments, the subject and/or animal is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon. In other embodiments, the subject and/or animal is a non-mammal, such, for example, a zebrafish. In some embodiments, the subject and/or animal may comprise fluorescently-tagged cells (with e.g. GFP). In some embodiments, the subject and/or animal is a transgenic animal comprising a fluorescent cell.

[0123] In some embodiments, the subject and/or animal is a human. In some embodiments, the human is a pediatric human. In other embodiments, the human is an adult human. In other embodiments, the human is a geriatric human. In other embodiments, the human may be referred to as a patient.

[0124] In certain embodiments, the human has an age in a range of from about 0 months to about 6 months old, from about 6 to about 12 months old, from about 6 to about 18 months old, from about 18 to about 36 months old, from about 1 to about 5 years old, from about 5 to about 10 years old, from about 10 to about 15 years old, from about 15 to about 20 years old, from about 20 to about 25 years old, from about 25 to about 30 years old, from about 30 to about 35 years old, from about 35 to about 40 years old, from about 40 to about 45 years old, from about 45 to about 50 years old, from about 50 to about 55 years old, from about 55 to about 60 years old, from about 60 to about 65 years old, from about 65 to about 70 years old, from about 70 to about 75 years old, from about 75 to about 80 years old, from about 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to about 95 years old or from about 95 to about 100 years old.

[0125] In other embodiments, the subject is a non-human animal, and therefore the invention pertains to veterinary use. In a specific embodiment, the non-human animal is a household pet. In another specific embodiment, the non-human animal is a livestock animal.

[0126] The invention provides kits that can simplify the administration of any agent described herein. An illustrative kit of the invention comprises any composition described herein in unit dosage form. In one embodiment, the unit dosage form is a container, such as a pre-filled syringe, which can be sterile, containing any agent described herein and a pharmaceutically acceptable carrier, diluent, excipient, or vehicle. The kit can further comprise a label or printed instructions instructing the use of any agent described herein. The kit may also include a lid speculum, topical anesthetic, and a cleaning agent for the administration location. The kit can also further comprise one or more additional agent described herein. In one embodiment, the kit comprises a container containing an effective amount of a composition of the invention and an effective amount of another composition, such those described herein.

[0127] The following definitions are used in connection with the invention disclosed herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of skill in the art to which this invention belongs.

[0128] As used herein, "a," "an," or "the" can mean one or more than one.

[0129] Further, the term "about" when used in connection with a referenced numeric indication means the referenced numeric indication plus or minus up to 10% of that referenced numeric indication. For example, the language "about 50" covers the range of 45 to 55.

[0130] An "effective amount," when used in connection with medical uses is an amount that is effective for providing a measurable treatment, prevention, or reduction in the rate of pathogenesis of a disease of interest.

[0131] As used herein, something is "decreased" if a read-out of activity and/or effect is reduced by a significant amount, such as by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or more, up to and including at least about 100%, in the presence of an agent or stimulus relative to the absence of such modulation. As will be understood by one of ordinary skill in the art, in some embodiments, activity is decreased and some downstream read-outs will decrease but others can increase.

[0132] Conversely, activity is "increased" if a read-out of activity and/or effect is increased by a significant amount, for example by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or more, up to and including at least about 100% or more, at least about 2-fold, at least about 3-fold, at least about 4-fold, at least about 5-fold, at least about 6-fold, at least about 7-fold, at least about 8-fold, at least about 9-fold, at least about 10-fold, at least about 50-fold, at least about 100-fold, in the presence of an agent or stimulus, relative to the absence of such agent or stimulus.

[0133] As referred to herein, all compositional percentages are by weight of the total composition, unless otherwise specified. As used herein, the word "include," and its variants, is intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the compositions and methods of this technology. Similarly, the terms "can" and "may" and their variants are intended to be non-limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features.

[0134] Although the open-ended term "comprising," as a synonym of terms such as including, containing, or having, is used herein to describe and claim the invention, the present invention, or embodiments thereof, may alternatively be described using alternative terms such as "consisting of" or "consisting essentially of."

[0135] As used herein, the words "preferred" and "preferably" refer to embodiments of the technology that afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the technology.

[0136] The amount of compositions described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose. Generally, for administering therapeutic agents (e.g. flagellin-based agents, flagellin-based agents (and/or additional agents) described herein) for therapeutic purposes, the therapeutic agents are given at a pharmacologically effective dose. A "pharmacologically effective amount," "pharmacologically effective dose," "therapeutically effective amount," or "effective amount" refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease. An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease. For example, administration of therapeutic agents to a patient suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the patient reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.

[0137] Effective amounts, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to about 50% of the population) and the ED50 (the dose therapeutically effective in about 50% of the population). The dosage can vary depending upon the dosage form employed and the route of administration utilized. The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50. In some embodiments, compositions and methods that exhibit large therapeutic indices are preferred. A therapeutically effective dose can be estimated initially from in vitro assays, including, for example, cell culture assays. Also, a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture, or in an appropriate animal model. Levels of the described compositions in plasma can be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The dosage can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.

[0138] In certain embodiments, the effect will result in a quantifiable change of at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 70%, or at least about 90%. In some embodiments, the effect will result in a quantifiable change of about 10%, about 20%, about 30%, about 50%, about 70%, or even about 90% or more. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.

[0139] In certain embodiments, a pharmacologically effective amount that will treat cancer will modulate the symptoms typically by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%. In illustrative embodiments, such modulations will result in, for example, statistically significant and quantifiable changes in the numbers of cancerous cells.

[0140] This invention is further illustrated by the following non-limiting examples.

EXAMPLES

Example 1

Preparation of the Model Vaccine

[0141] Alum adjuvant (IMJECT ALUM, THERMO) was used in combination with CBLB502 to challenge the mice with a model antigen, ovalbumin (OVA). Vaccine was comprised of the following components as shown in TABLE A:

TABLE-US-00002 Component Amount (per mouse) Ovalbumin 10 mg CBLB502 1 ug/10 ug Alum Adjuvant 500 ug

[0142] To achieve excellent absorption CBLB502 (either 1 .mu.g or 10 .mu.g) was mixed with 10 mg of OVA and 500 .mu.g of Alum adjuvant for 30 minutes at 300 rpm at room temperature.

Example 2

Mouse Immunization Study

[0143] C57BI/6 male mice (10 weeks of age, n=6 for each experiment) were used for injection. Mice were divided into five groups with six animals in each group (n=6). Mice were injected with 100 .mu.l of above described vaccine in each of the hind legs (200 .mu.l total per mouse) as shown in TABLE B.

TABLE-US-00003 Ovalbumin CBLB502 Alum Adjuvant Group 1 Group 2 10 mg Group 3 10 mg 500 ug Group 4 10 mg 1 ug 500 ug Group 5 10 mg 10 ug 500 ug

Two weeks after the initial immunization mice were challenged with an additional booster following the same setup as the original injection. Plasma was collected one, two and four weeks after booster via mandibular vein. Using an ELISA based assay total IgG, IgG1, IgG2a, IgG2b and IgG3 were measured. Results are shown in FIGS. 2-3. In the figures, Group 1 is also called "Untreated;" Group 2 is also called "OVA," Groups 3 is also called "OVA+Alum," Group 4 is also called "SA 1 .mu.g," and Group 5 is also called "SA 10 .mu.g."

[0144] FIG. 2 shows ELISA data for the average response of the five aforementioned mouse treatment groups at the time point of 1 week post-boost. FIG. 3 shows ELISA data for the average response of the five aforementioned mouse treatment groups at the time point of 2 weeks post-boost. FIG. 4 shows ELISA data for the average response of the five aforementioned mouse treatment groups at the time point of 4 weeks post-boost.

Example 3

Evaluation of CBLB502 Binding to ALHYDROGEL

[0145] The binding capacity of ALHYDROGEL for CBLB502 was evaluated. ALHYDROGEL adjuvant 2%, aluminium hydroxide wet gel (colloidal) suspension (INVIVIGEN Catalog #vac-alu-250), was mixed with CBLB502 at different volume ratios, resulting in 10 to 52% ALHYDROGEL suspension in the reaction. CBLB502 concentration was maintained at 10 .mu.g/ml, corresponding to a 1 .mu.g/100 .mu.l inoculation dose (100 .mu.l inoculation volume is the recommended maximum volume for subcutaneous injection of antigen/adjuvant mixtures per injection site for mice). After overnight incubation at 4.degree. C., the tubes were centrifuged to sediment ALHYDROGEL and unbound CBLB502, remaining in solution was measured by ELISA. The amounts of adsorbed CBLB502 were calculated as difference between total protein added to the mixture and unbound CBLB502 (TABLE C). The maximum adsorption of CBLB502, more than 99.9% bound, was observed when the reactions were formulated with 40 to 52 .mu.l ALHYDROGEI/100 .mu.l; at lower ratios, the binding efficiency decreased gradually to about 83% at 10 .mu.ml/100 .mu.l ALHYDROGEL suspension.

TABLE-US-00004 TABLE C CBLB502 adsorption at different ALHYDROGEL 2% volume ratios. The binding reactions were composed of CBLB502, PBS and the indicated volumes of ALHYDROGEl adjuvant 2%. ALHYDROGEL 2% CBLB502 dose Total CBLB502 Unbound Bound Bound .mu.l/100 .mu.l .mu.g/100 .mu.l ng/ml ng/ml ng/ml (%) 1 52 1 10000 2.1 9997.9 99.98 2 50 1 10000 1.6 9998.4 99.98 3 40 1 10000 2.9 9997.1 99.97 4 30 1 10000 22.7 9977.3 99.77 5 20 1 10000 173.4 9826.6 98.27 6 10 1 10000 1692.5 8307.5 83.07

[0146] CBLB502 binding to ALHYDROGEL was also evaluated at different CBLB502 doses. Adsorption of CBLB502 to ALHYDROGEL (52 .mu.l/100 .mu.l ALHYDROGEL adjuvant 2%) was determined at CBLB502 doses, ranging from approximately 0.02 to 20 .mu.g per 100 .mu.l. The reactions were incubated as described above and unbound CBLB502 was measured by ELISA. The results (TABLE D) demonstrated that almost complete binding of the drug to ALHYDROGEL, 99.82 to 99.99% bound, was accomplished at all tested CBLB502 concentrations.

TABLE-US-00005 TABLE D Efficiency of CBLB502 binding to ALHYDROGEl in PBS. The incubations were performed with CBLB502 at the indicated doses in PBS and 52 .mu.l/100 .mu.l ALHYDROGEL adjuvant 2%. CBLB502 dose Total CBLB502 Unbound Bound Bound .mu.g/100 .mu.l ng/ml ng/ml ng/ml (%) 1 20 200000 199.3 199800.7 99.90 2 5 50000 90.6 49909.4 99.82 3 1.25 12500 0.79 12499.2 99.99 4 0.31 3125.0 0.029 3124.97 99.99 5 0.078 781.25 0.023 781.23 99.99 6 0.02 195.31 0.011 195.30 99.99

[0147] CBLB502 binding to ALHYDROGEL in the presence of TT-SMA vaccine was evaluated. Binding efficiency of CBLB502 to ALHYDROGEL was tested in the presence of a vaccine candidate TT-SMA, succinyl methamphetamine (SMA) hapten conjugated to tetanus toxoid. In a separate study, shown below, this vaccine was administered to mice at a 32 .mu.g/100 .mu.l dose to compare efficacy with and without CBLB502. This TT-SMA dose was co-incubated with CBLB502 (0.02 to 20 .mu.g/100 .mu.l) and ALHYDROGEL (52 .mu.l/100 .mu.l) under standard conditions and unbound CBLB502 was measured by ELISA. The binding efficiency was 99.7 to 99.9% at all tested CBLB502 concentrations, indicating that CBLB502 adsorption to ALHYDROGEL was unaffected with addition of TT-SMA to the reaction mixture

TABLE-US-00006 TABLE E CBLB502 binding to ALHYDROGEL in the presence of TT-SMA. The incubations were performed with CBLB502 at the indicated doses in PBS, 52 .mu.l/100 .mu.l ALHYDROGEL adjuvant 2% and 32 .mu.g/100 .mu.l TT-SMA conjugate. CBLB502 dose Total CBLB502 Unbound Bound Bound .mu.g/100 .mu.l ng/ml ng/ml ng/ml (%) 1 20 200000 668.88 199331.1 99.67 2 5 50000 50.21 49949.8 99.90 3 1.25 12500 11.44 12488.6 99.91 4 0.31 3125.0 1.65 3123.4 99.95 5 0.078 781.25 0.13 781.1 99.98 6 0.02 195.31 0.06 195.2 99.96

Example 4

Analysis of In Vitro CBLB502 Activity After Adsorption to ALHYDROGEL

[0148] An activity assay of CBLB502/ALHYDROGEL using 293-hTLR5-LacZ reporter cells was undertaken. Biological activity of CBLB502 after adsorption to ALHYDROGEL was tested using an in vitro assay which measures activation of a NF-.kappa.B-controlled reporter enzyme, .beta.-galactosidase, in HEK293-hTLR5::NF-.kappa.N-lacZ (293-hTLR5-LacZ) cells. Since 293-hTLR5-LacZ cells express only one cell membrane-bound toll-like receptor, human TLR5, CBLB502 activity could be determined without interference from other toll-like receptor ligands such as LPS (endotoxin).

[0149] Specific induction of the .beta.-galactosidase reporter by CBLB502/ALHYDROGEL was demonstrated after incubating the cells with a serially diluted CBLB502/ALHYDROGEL formulation (5 .mu.g/100 .mu.l), starting with a 2000-fold dilution in cell growth media and resulting in the concentration range of ALHYDROGEL-adsorbed

[0150] CBLB502 from 25 to 0.004 ng/ml (FIG. 5). The maximum .beta.-galactosidase activity was observed at 0.93 ng/ml ALHYDROGEL-adsorbed CBLB502; this value was consistent with typical results of the assay using soluble CBLB502 where the reporter enzyme activity would normally peak around 1 ng/ml. ALHYDROGEL alone tested at same dilutions did not induce the reporter. Therefore, it could be concluded, inter a/ia, that CBLB502 retains its biological activity after adsorption to ALHYDROGEL and becomes readily available for interaction with its target receptor (TLR5) under regular cell culture conditions.

[0151] Next, CBLB502/ALHYDROGEL suspensions were prepared at CBLB502 inoculation doses ranging from 2.5 to 0.00015 .mu.g/100 .mu.l and were added to 293-hTLR5-LacZ cells at 200-fold dilution (FIG. 6). NF-.kappa.B-inducing activity followed a typical dose-response pattern and was measured at sub-nanogram doses of CBLB502/ALHYDROGEL (less than 0.001 .mu.g/100 .mu.l), indicating that at such low doses, CBLB502 was not irreversibly bound to the alum adjuvant and remained active.

[0152] An activity titration of CBLB502/ALHYDROGEL at different CBLB502 doses was undertaken. CBLB502/ALHYDROGEL suspensions were titrated in cell culture media and incubated with 293-hTLR5-LacZ cells. CBLB502 standards were included in the assay to compare the recovered activity. The resulting reporter enzyme activity was plotted against theoretical concentrations of ALHYDROGEL-bound CBLB502, assuming that the protein was completely available (FIG. 7).

[0153] The results of titration assay demonstrated that at a formulation dose of 20 .mu.g/100 .mu.l, the activity of CBLB502 followed the expected concentrations, essentially matching the activity of soluble standards. However, reduction of the dose 64- and 256-fold to respectively, about 0.31 and 0.078 .mu.g/100 .mu.l, resulted in lower relative recovery of NF-.kappa.B-inducing activity to approximately 15-30%. This apparent loss of CBLB502 activity could be due to stronger binding of the particular amounts of the protein relative to the amounts of alum in the formulation. These fixed amounts could represent a small fraction of total CBLB502 at the higher doses such as 20 .mu.g/100 .mu.l and would not affect significantly the measured activity. However, at lower doses, this tightly adsorbed fraction may become substantial compared to the total protein, leading to a lower measurable activity of CBLB502

Example 5

Assessment of CBLB502/ALHYDROGEL Short-Term Storage Stability at 4.degree. C.

[0154] A formulation of 1 .mu.g/100 .mu.l CBLB502 (52 .mu.l/100 .mu.l ALHYDROGEL 2%) was prepared and tested for activity after 2 and 6 days storage at 4.degree. C. The results of CBLB502 activity assay using 293-hTLR5-LacZ reporter cells are shown in FIG. 8. Based on comparison with the soluble CBLB502 standard, in can be concluded that NF-.kappa.B-inducing activity of ALHYDROGEL-adsorbed CBLB502 remained unchanged after 6 days under the storage conditions.

Example 6

Evaluation of CBLB502 Dissociation from ALHYDROGEL in PBS and Cell Media

[0155] Aliquots of CBLB502/ALHYDROGEL (1 .mu.g/100 .mu.l dose; 52 .mu.l/100 .mu.l ALHYDROGEL 2%) were re-suspended in PBS or cell media (DMEM supplemented with 10% FBS) and incubated for 3 hr at 22.degree. C. and 37.degree. C. After centrifugation to remove ALHYDROGEL, dissociated CBLB502 was measured in supernatants by ELISA. The calculation of CBLB502 amounts that were recovered during incubation demonstrated that the protein remained stably associated with ALHYDROGEL in PBS; however, in cell media, 28 and 53% CBLB502 was released from the complex at 22.degree. C. and 37.degree. C., respectively (TABLE F). Such rapid dissociation from ALHYDROGEL in media may be facilitated by serum proteins which could displace CBLB502 from the complex with alum, explaining how the protein becomes readily available in the cell-based activity assay.

TABLE-US-00007 TABLE F CBLB502 recovery from ALHYDROGEL after incubation in PBS and cell media 22.degree. C. 37.degree. C. Incubation CBLB502 dose Total CBLB502 Recovered Desorption Recovered Desorption conditions .mu.g/100 .mu.l ng/ml ng/ml (%) ng/ml (%) PBS 1 10000 2.3 0.02 33.2 0.33 Media 1 10000 2807.6 28.1 5300.9 53.0

Example 7

Quantitation of CBLB502 and Cytokine Levels in Mouse Serum After Subcutaneous Administration of CBLB502/ALHYDROGEL

[0156] An animal study was conducted to evaluate feasibility of methods to determine the levels of CBLB502 and cytokines in serum after administration of a CBLB502/ALHYDROGEL formulation. The study design is presented in TABLE G. In this study, mice were injected subcutaneously with a 1 .mu.g dose CBLB502 adsorbed to 52 .mu.l/100 .mu.l ALHYDROGEL 2% and serum samples were collected between 0.5 and 24 hr post inoculation.

TABLE-US-00008 TABLE G Study design. Time Age Injection Point, Group Group Strain volume, blood No. Size Sex Treatment .mu.l collection Evaluation 1 3 8 wk old ALHYDROGEL/PBS, sc 100 1 hr Serum prepared from 2 3 C57BL/6 ALHYDROGEL/PBS/CBLB502, 100 30 min collected blood and 3 3 Female (1 .mu.g/100 .mu.l CBLB502; 52 .mu.l/ 100 1 h analyzed for 4 3 100 .mu.l ALHYDROGEL 2%) 100 2 h entolimod 5 3 sc 100 4 h concentration and 6 3 100 8 h cytokine levels by 7 3 100 24 h ELISA

[0157] Serum concentrations of CBLB502 were determined by ELISA and were found at measurable levels in all groups of animals inoculated with CBLB502/ALHYDROGEL. The pharmacokinetic profile representing per-group mean serum CBLB502 concentrations is shown in FIG. 9. The maximum mean CBLB502 concentration, 0.516 ng/ml, was observed at the first blood collection time point, 0.5 hr post administration; the minimum concentration was 0.012 ng/ml at 24 hr. Half-time elimination of CBLB502 was calculated at 2.4 hr. As discussed above, CBLB502 dissociated rapidly from the complex with ALHYDROGEL after incubation in cell media, containing 10% fetal bovine serum. Therefore, it should be expected to see the protein released from alum into animal bloodstream shortly after inoculation.

[0158] The concentrations of three cytokines, KC, G-CSF and IL-6, were measured in the collected mouse serum samples by ELISA (FIG. 10). Rapid induction of KC and IL-6 was detected 1 hr after CBLB502/ALHYDROGEL administration; the maximum per-group mean concentrations, 29624 and 479 pg/ml, respectively, were determined at 2 hr time point. After reaching maximum, the blood levels of these cytokines decreased to baseline at 4 to 8 hr post injection. The serum G-CSF concentration increased about an hour later compared to KC and IL-6 and was maximal between 2 and 4 hr after CBLB502/ALHYDROGEL administration (7141 and 7169 pg/ml per-group mean concentrations at 2 and 4 hr, respectively). However, CBLB502-induced G-CSF level was decreasing at a slower rate, remaining above baseline at 24 hr time point. In general, the kinetics of cytokine induction after CBLB502/ALHYDROGEL administration was similar to the kinetics observed after injection of the soluble CBLB502 preparations, suggesting consistent effects of this drug formulation.

Example 8

CBLB502 Adjuvant With Methamphetamine Vaccine

[0159] This study evaluated CBLB502 adjuvant at a 32 .mu.g dose of human methamphetamine vaccine (SMA-TT) to achieve high and long lasting levels of anti-MA antibody in mice. A low to high dose of CBLB502 ranging from 0.03 to 20 .mu.g with TT-SMA and alum was studied. Ten groups (n=5) of Balb/c female mice were employed to test 0, 0.03, 0.1, 0.3, 1, 3, 10, 20 .mu.g of 502 in combination with 32 .mu.g of TT-SMA and 1.5 mg alum compared to unvaccinated controls and TT-SMA with 502 alone. All vaccinated groups were administered two boosters, at 3 and 6 weeks after the initial vaccination. Levels of anti-MA IgG were assessed by ELISA in pooled sera samples collected at 2, 4, and 6 weeks after initial vaccination. The antibody levels were higher at 0.03 to 0.3 .mu.g 502 in comparison to the higher doses (1 to 20 .mu.g) of 502. In this experiment, antibody levels were 2 fold higher in the groups with 0.1 .mu.g of 502 in combination with TT-SMA and alum (group 4) than in the comparison group with TT-SMA and alum alone (group 1) and approx. 4 fold higher when compared to a group with TT-SMA and 502 alone (group 2), as demonstrated in FIG. 11 (panel A). Anti-502 antibodies in the same sera sample were also evaluated. As shown in FIG. 11 (panel B), the level of anti-502 antibodies was minimal at the low dose range of 502 and increases at higher doses of 502.

Example 9

Generation of Vaccines With Various Antigens

[0160] In this Example, the composition of an adjuvant component for adjuvant-enhanced vaccine is established by testing a range of doses of CBLB502 and CBLB502 optionally combined with an antigen, such as, by way of non-limitation, NOD1 agonist C12-iE-DAP. Additionally, characterization of the effects of these agents on humoral immune response to a model antigen (ovalbumin) is undertaken.

[0161] As shown above, aluminum hydroxide and CBLB502 form a complex which, without wishing to be bound by theory, is stabilized by electrostatic forces as substances with opposite charges in aqueous medium. To test relative efficacy of different compositions of the adjuvant component of the vaccine, a standard dose of aluminum is used (1.5 .mu.g per injection) loaded with a range of doses of CBLB502 (up to 30 .mu.g and including 10 .mu.g, 3 .mu.g, 1 .mu.g, 0.3 .mu.g and 0.1 .mu.g). CBLB502 in aqueous solution is added to the alum suspension in PBS and stirred for 10 min at room temperature. Aluminum hydroxide is then spun down by centrifugation and traces of CBLB502 in supernatants are determined using two quantitative analytical assays: (i) ELISA-based and (ii) reporter cell based (TLR5-positive 293 cells carrying NF-.kappa.B responsive reporter and calibrated for detection of CBLB 502 in the medium). In light of, inter alia, the above Examples, it is expected that a substantial fraction of CBLB 502 will be stably bound to alum under these conditions and within the chosen range of doses of TLR5 agonists.

[0162] To determine whether this adjuvant remains localized at the vaccine injection site, adult BALB/c female mice (n=10) carrying in their germ line firefly luciferase cDNA under the control of NF-.kappa.B-responsive promoter will be used. These "NF-.kappa.B reporter mice" are a sensitive tool for the detection of release of CBLB502 from the injection site by monitoring the luciferase activity in TLR5-positive tissues such as liver or small intestine. Only one dose of CBLB502-containing adjuvant formulation will be used that corresponds to the highest dose that demonstrated stability as a composition with Alum in vitro (presumably 30 .mu.g). Two doses of free CBLB502 (1 and 3 .mu.g in aqueous solution, s.c. injection) will be used for comparison as positive controls of systemically distributed TLR5 agonist. Luciferase detection will be done using a luminescent imager in vivo following luciferin injection at 2, 4, 6 and 18 hours post injection of the adjuvant. For a more accurate and sensitive detection, 3 animals from each group are sacrificed 6 hours post injection of the adjuvant formulation and tissues will be collected from the injection site, lymph nodes nearest to injection site and the liver. The level of luciferase activity indicative of the presence of CBLB 502 is quantitated in these tissue samples following tissue lysis. In addition to functional detection of CBLB 502 based on its expected NF-.kappa.B-inducing activity, an alternative analytical method of an established sensitive ELISA assay for direct detection of CBLB502 in tissue extracts is used.

[0163] Adjuvant formulations containing the above-described range of doses of CBLB502 are mixed with 10 mg of ovalbumin and vaccination is performed, as described herein, followed by the ELISA determination of titers of different classes of anti-albumin IgG (IgG1, IgG2a, IgG2b and IgG3) antibodies. The results are compared with "Alum only" control. Determination of the effects on different IgG types provides definition of the degrees of engagement of different immunization paths (e.g. T.sub.H1- versus T.sub.H2-mediated routes) by the adjuvant.

[0164] After determination of the composition of the adjuvant (in terms of anti-ovalbumin antibody inducing efficacy), additional enhancement of immunization is tested by adding into the formulation a NOD1 agonist, C12-iE-DAP.

[0165] Also, determination of vaccine efficacy at different CBLB 502 doses to generate antibodies to antigen is undertaken in mice. Female mice are chosen because they have stronger immune responses than male mice and BALB/c mice are a commonly used strain in immunological studies due to their robust immune responses. At the beginning of the study, mice weigh about 25 g and are group-housed (5 per cage) in standard acrylic cages (7''.times.11''.times.5'') with corncob bedding polycarbonate and tops. Mice will have ad libitum access to food (Harlan) and water. The vivarium will be maintained at 22.+-.1.degree. C. and on a 12:12 light/dark cycle (lights on at 6 AM). All experimental procedures are approved by the Institutional Animal Care and Use Committee (IACUC) and are within the guidelines delineated in the Guide for the Care and Use of Laboratory Animals.

[0166] Mice are intramuscularly injected with the vaccine in the gluteal muscle. Each group is optionally immunized with a booster dose with the same vaccine formulation at 3 and 6 weeks post initial immunization. If persistent antibody levels are not maintained for at least 4 weeks, an additional immunization will be given at week 10.

[0167] Blood is drawn at 14, 28, 42, 56 and 84 days post initial immunization and allowed to clot at room temperature for 2 hours. Serum is collected after centrifugation at 4000 rpm for 15 min. Samples are stored at -80 degrees until ready to run the enzyme linked immunosorbent assays (ELISA). In the context of a vaccine with antigen X, anti-antigen X specific antibodies are assessed by ELISAs. To measure the antibodies, ELISA plates (Immulon 2HB, Daigger, Vernon Hills, Ill.) are coated overnight in carbonate buffer (0.05 M; pH 9.6) using fish gelatin, which is a heterologous carrier protein, as the conjugate partner for SMA. Pooled or individual serum samples are added to plates in 2 fold serial dilutions starting at 1K in phosphate buffered saline (PBS)-Tween (0.1%) and incubated for 2 hours. Plates are washed with PBS-Tween prior to adding goat anti-mouse IgG conjugated to horse-radish peroxidase (HRP) (Southern Biotech, Birmingham, Ala.). Plates are incubated for another 30 min and washed before adding substrate (Tetramethylbenzidine, Sigma, St. Louis, Mo.). Plates are incubated for 45 min in the dark prior to stopping the reaction with 1M HCl. The optical density (OD) of the resulting dark spots on the plates from the antibody with antigen X linking are used to measure titer levels on a microplate reader (iMark Microplate Absorbance Reader) using Microplate Manager v 6.1 software.

[0168] ELISA data is analyzed using SigmaPlot (Systat Software Inc.) and background antibody binding to the carrier alone will be subtracted from each sample. Comparisons are made in each plate with a standard curve of purified mouse IgG (Sigma) bound directly in the wells in serial dilution.

Example 10

Comparison of CBLB502-Based Adjuvants/Vaccines With Flagellin-Based Adjuvants/Vaccines

[0169] The CBLB502/alum adjuvant of the above Examples is tested head to head against a flagellin/alum adjuvant using the methods and study design of, for instance, Example 9 (optionally with an antigen). Further, the alum binding and dissociation studies, as well as the mouse evaluation studies, all described in the above Examples, are reapeated with a flagellin/alum adjuvant for comparison to the CBLB502/alum adjuvant. The efficacy of the CBLB502 variant, i.e., CBLB502-S33MX is also tested.

[0170] In one comparison experiment, a group of mice (n=6) is immunized with TT-SMA, which is a methamphetamine vaccine and is used illustratively, co-adsorbed onto Alhydrogel with either flagellin, CBLB502, or CBLB502-S33MX. Immunication is carried out on days 0, 14, and 28 of the study. Each immunization dose includes 32 .mu.g of TT-SMA and adjuvants as follows: Group 1: 0.03 .mu.g flagellin, Group 2: 0.1 .mu.g flagellin, Group 3: 0.3 .mu.g flagellin, Group 4: 1 .mu.g flagellin, Group 5: 0.03 .mu.g CBLB502, Group 6: 0.1 .mu.g CBLB502, Group 7: 0.3 .mu.g CBLB502, Group 8: 1 pg CBLB502, Group 9: 0.03 g CBLB502-S33MX, Group 10: 0.1 pg CBLB502-S33MX, Group 11: 0.3 .mu.g CBLB502-S33MX, and Group 12: 1 .mu.g CBLB502-S33MX.

[0171] Serum samples are collected and analyzed on days -1 (pre-immune serum), 14 (post-prime), 28 (post first boost), and 35 (post second boost). For example, the serum samples are analzyed for the levels of anti-methamphetamine and anti-entolimod antibodies. Analysis indicates that CBLB502/alum and CBLB502-S33MX/alum cause a broader, more diverse, more robust and longer immunostimulatory effect than flagellin/alum. In addition, CBLB502/alum and CBLB502-S33MX/alum activate both T.sub.H1 and T.sub.H2-mediated immune response and a greater T.sub.H1-mediated immune response than flagellin/alum.

Equivalents

[0172] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

[0173] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Incorporation by Reference

[0174] All patents and publications referenced herein are hereby incorporated by reference in their entireties.

[0175] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

[0176] As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections.

REFERENCES

[0177] 1. Yoon S I, Kurnasov O, Natarajan V, Hong M, Gudkov A V, Osterman A L, Wilson I A., 2012. Structural Basis of TLR5-Flagellin Recognition and Signaling. Science 335:859-864 (PMID: 22344444)

[0178] 2. Smith K D, Andersen-Nissen E, Hayashi F, Strobe K, Bergman M A, Barrett S L, Cookson B T, Aderem A. 2003. Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat Immunol. 4:1247-53 (PMID: 14625549)

[0179] 3. Mizel, S. B., A. P. West, R. R. Hantgan. 2003. Identification of a sequence in human Toll-like receptor 5 required for the binding of Gram-negative flagellin. J. Biol. Chem. 278:23624-23629 (PMID: 12711596)

[0180] 4. Murthy, K. G., Deb, A., Goonesekera, S., Szabo, C. & Salzman, A. L. (2004) J. Biol. Chem. 279:5667-5675 (PMID: 14634022)

[0181] 5. Andersen-Nissen E., Smith K. D., Strobe K. L., Barrett S. L., Cookson B. T., Logan S. M., Aderem A.(2005) Evasion of Toll-like receptor 5 by flagellated bacteria. Proc. Natl. Acad. Sci. U.S.A. 102: 9247-9252 (PMID: 15956202)

[0182] 6. Andersen-Nissen E, Smith K D, Bonneau R, Strong R K, Aderem A. 2007. A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin. J Exp Med. 204:393-403 (PMID: 17283206)

[0183] 7. Burdelya L G, Krivokrysenko V I, Tallant T C, Strom E, Gleiberman A S, Gupta D, Kurnasov O V, Fort F L, Osterman A L, Didonato J A, Feinstein E, Gudkov A V., 2008. An agonist of Toll-like receptor 5 has radioprotective activity in mouse and primate models. Science 320:226-230 (PMID: 18403709).

[0184] 8. Huleatt J W, Nakaar V, Desai P, Huang Y, Hewitt D, Jacobs A, Tang J, McDonald W, Song L, Evans R K et al. 2008. Potent immunogenicity and eff0icacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TRL5 ligand flagellin. Vaccine. 26:201-214.

Sequence CWU 1

1

2521505PRTSalmonella dublin 1Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn 1 5 10 15 Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg Leu 20 25 30 Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 50 55 60 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 65 70 75 80 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 85 90 95 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 100 105 110 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 115 120 125 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 130 135 140 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 145 150 155 160 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 165 170 175 Gly Pro Lys Glu Ala Thr Val Gly Asp Leu Lys Ser Ser Phe Lys Asn 180 185 190 Val Thr Gly Tyr Asp Thr Tyr Ala Ala Gly Ala Asp Lys Tyr Arg Val 195 200 205 Asp Ile Asn Ser Gly Ala Val Val Thr Asp Ala Ala Ala Pro Asp Lys 210 215 220 Val Tyr Val Asn Ala Ala Asn Gly Gln Leu Thr Thr Asp Asp Ala Glu 225 230 235 240 Asn Asn Thr Ala Val Asp Leu Phe Lys Thr Thr Lys Ser Thr Ala Gly 245 250 255 Thr Ala Glu Ala Lys Ala Ile Ala Gly Ala Ile Lys Gly Gly Lys Glu 260 265 270 Gly Asp Thr Phe Asp Tyr Lys Gly Val Thr Phe Thr Ile Asp Thr Lys 275 280 285 Thr Gly Asp Asp Gly Asn Gly Lys Val Ser Thr Thr Ile Asn Gly Glu 290 295 300 Lys Val Thr Leu Thr Val Ala Asp Ile Ala Thr Gly Ala Ala Asp Val 305 310 315 320 Asn Ala Ala Thr Leu Gln Ser Ser Lys Asn Val Tyr Thr Ser Val Val 325 330 335 Asn Gly Gln Phe Thr Phe Asp Asp Lys Thr Lys Asn Glu Ser Ala Lys 340 345 350 Leu Ser Asp Leu Glu Ala Asn Asn Ala Val Lys Gly Glu Ser Lys Ile 355 360 365 Thr Val Asn Gly Ala Glu Tyr Thr Ala Asn Ala Thr Gly Asp Lys Ile 370 375 380 Thr Leu Ala Gly Lys Thr Met Phe Ile Asp Lys Thr Ala Ser Gly Val 385 390 395 400 Ser Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala 405 410 415 Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val 420 425 430 Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr 435 440 445 Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile 450 455 460 Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln 465 470 475 480 Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val 485 490 495 Pro Gln Asn Val Leu Ser Leu Leu Arg 500 505 2329PRTArtificial SequenceSynthetic sequence 2Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr 1 5 10 15 Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Asp Asp Asp Lys Asp 20 25 30 Pro Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln 35 40 45 Asn Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg 50 55 60 Leu Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly 65 70 75 80 Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln 85 90 95 Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu 100 105 110 Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu 115 120 125 Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser 130 135 140 Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser 145 150 155 160 Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln 165 170 175 Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp 180 185 190 Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val 195 200 205 Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met 210 215 220 Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala 225 230 235 240 Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val 245 250 255 Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr 260 265 270 Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile 275 280 285 Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln 290 295 300 Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val 305 310 315 320 Pro Gln Asn Val Leu Ser Leu Leu Arg 325 321DNAArtificial SequenceSynthetic sequence 3taatacgact cactataggg g 21420DNAArtificial SequenceSynthetic sequence 4attgcgcaga ccactgaagg 2056PRTArtificial SequenceSynthetic sequence 5Leu Val Pro Arg Gly Ser 1 5 65PRTArtificial SequenceSynthetic sequence 6Asp Asp Asp Asp Lys 1 5 713PRTArtificial SequenceSynthetic sequence 7Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala 1 5 10 86PRTArtificial SequenceSynthetic sequence 8Glu Asp Ala Asp Tyr Ala 1 5 914PRTArtificial SequenceSynthetic sequence 9Ala Ala Ser Ala Gly Ala Gly Gln Gly Gly Gly Gly Ser Gly 1 5 10 1014PRTArtificial SequenceSynthetic sequence 10Glu Gly Lys Ser Ser Gly Ser Gly Ser Glu Ser Lys Ser Thr 1 5 10 1122PRTArtificial SequenceSynthetic sequence 11Gly Gly Gly Arg Thr Ser Ser Ser Ala Ala Ser Ala Gly Ala Gly Gln 1 5 10 15 Gly Gly Gly Gly Ser Gly 20 124PRTArtificial SequenceSynthetic sequence 12Gly Pro Ser Gly 1 1312PRTArtificial SequenceSynthetic sequence 13Gly Ser Ala Gly Ser Ala Ala Gly Ser Gly Glu Phe 1 5 10 144PRTArtificial SequenceSynthetic sequence 14Gly Ser Pro Gly 1 1518PRTArtificial SequenceSynthetic sequence 15Lys Glu Ser Gly Ser Val Ser Ser Glu Gln Leu Ala Gln Phe Arg Ser 1 5 10 15 Leu Asp 1616PRTArtificial SequenceSynthetic sequence 16Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met Gly 1 5 10 15 17300PRTArtificial SequenceSynthetic sequence 17Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr 1 5 10 15 Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30 Ser Ala Lys Asp Pro Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp 35 40 45 Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly 50 55 60 Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln 65 70 75 80 Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val 85 90 95 Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp 100 105 110 Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp 115 120 125 Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln 130 135 140 Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile 145 150 155 160 Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly 165 170 175 Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu 180 185 190 Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys 195 200 205 Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val 210 215 220 Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser 225 230 235 240 Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg 245 250 255 Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser 260 265 270 Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala 275 280 285 Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Arg 290 295 300 1848DNAArtificial SequenceSynthetic sequence 18gcagattctg cagcaggctg gttgataatc tggcgcaggc taaccagg 481960DNAArtificial SequenceSynthetic sequence 19tctaaagcgc agattctgca gcaggctggt acttccgttc tggcgcaggc taaccaggtt 602048DNAArtificial SequenceSynthetic sequence 20cctggttagc ctgcgccaga ttatcaacca gcctgctgca gaatctgc 4821936DNAArtificial SequenceSynthetic sequence 21taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg cggggttctc atcatcatca tcatcatggt 120atggctagca tgactggtgg acagcaaatg ggtcgggatc tgtacgacct ggttccgcgc 180ggtagcgcga aggatccgtc tggtctgcgt atcaacagcg cgaaagacga tgcggcaggc 240caggcgattg ctaaccgctt cacttctaat atcaaaggtc tgactcaggc ttcccgtaac 300gctaacgacg gcatttctat tgcgcagacc actgaaggtg cgctgaatga aatcaacaac 360aacctgcagc gtgtgcgtga gttgtctgtt caggccacta acgggactaa ctctgattcc 420gatctgaaat ctatccagga tgaaattcag caacgtctgg aagaaatcga tcgcgtttct 480aatcagactc aatttaacgg tgttaaagtc ctgtctcagg acaaccagat gaaaatccag 540gttggtgcta acgatggtga aaccattacc atcgatctgc aaaaaattga tgtgaaaagc 600cttggccttg atgggttcaa tgttaattcc ccgggaattt ccggtggtgg tggtggaatt 660ctagactcca tgggtacatt aatcaatgaa gacgctgccg cagccaagaa aagtaccgct 720aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 780ggggcaattc aaaaccgttt tgattcagcc attaccaacc ttggcaatac ggtaaccaat 840ctgaactccg cgcgtagccg tatcgaagat gctgactatg caacggaagt ttctaatatg 900tctaaagcgc agattctgca gcaggctggt tgataa 93622281PRTArtificial SequenceSynthetic sequence 22Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr 1 5 10 15 Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30 Ser Ala Lys Asp Pro Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp 35 40 45 Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly 50 55 60 Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln 65 70 75 80 Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val 85 90 95 Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp 100 105 110 Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp 115 120 125 Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln 130 135 140 Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile 145 150 155 160 Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly 165 170 175 Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu 180 185 190 Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys 195 200 205 Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val 210 215 220 Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser 225 230 235 240 Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg 245 250 255 Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser 260 265 270 Lys Ala Gln Ile Leu Gln Gln Ala Gly 275 280 23329PRTArtificial SequenceSynthetic sequence 23Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn 1 5 10 15 Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg Leu 20 25 30 Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 50 55 60 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 65 70 75 80 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 85 90 95 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 100 105 110 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 115 120 125 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 130 135 140 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 145 150 155 160 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 165 170 175 Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met Gly 180 185 190 Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala Asn 195 200 205 Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg 210 215 220 Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn 225 230 235 240 Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu 245 250 255 Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile 260 265 270 Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro 275 280 285 Gln Asn Val Leu Ser Leu Leu Val Pro Arg Gly Ser His His His His 290 295 300 His His Gly Met Ala Ser Met Thr Gly Gly Gln Gln Met Gly Arg Asp 305 310 315 320 Leu Tyr Asp Asp Asp Asp Lys Asp Pro 325 241005DNAArtificial SequenceSynthetic sequence 24atggcacaag tcattaatac aaacagcctg tcgctgttga cccagaataa cctgaacaaa 60tctcagtcct cactgagttc cgctattgag cgtctgtcct ctggtctgcg tatcaacagc 120gcgaaagacg atgcggcagg ccaggcgatt gctaaccgct tcacttctaa tatcaaaggt 180ctgactcagg cttcccgtaa cgctaacgac ggcatttcta ttgcgcagac cactgaaggt 240gcgctgaatg aaatcaacaa caacctgcag cgtgtgcgtg agttgtctgt tcaggccact 300aacgggacta actctgattc cgatctgaaa tctatccagg atgaaattca gcaacgtctg 360gaagaaatcg atcgcgtttc taatcagact caatttaacg gtgttaaagt cctgtctcag 420gacaaccaga tgaaaatcca ggttggtgct aacgatggtg aaaccattac catcgatctg 480caaaaaattg atgtgaaaag ccttggcctt gatgggttca atgttaattc cccgggaatt 540tccggtggtg gtggtggaat tctagactcc atgggtacat taatcaatga

agacgctgcc 600gcagccaaga aaagtaccgc taacccactg gcttcaattg attctgcatt gtcaaaagtg 660gacgcagttc gttcttctct gggggcaatt caaaaccgtt ttgattcagc cattaccaac 720cttggcaata cggtaaccaa tctgaactcc gcgcgtagcc gtatcgaaga tgctgactat 780gcaacggaag tttctaatat gtctaaagcg cagattctgc agcaggctgg tacttccgtt 840ctggcgcagg ctaaccaggt tccgcaaaac gtcctctctt tactggttcc gcggggttct 900catcatcatc atcatcatgg tatggctagc atgactggtg gacagcaaat gggtcgggat 960ctgtacgacg atgacgataa ggatccgtaa gtcgacaagc ttgcg 10052531DNAArtificial SequenceSynthetic sequence 25cgaaagacca tatggcaggc caggcgattg c 312633DNAArtificial SequenceSynthetic sequence 26cgcaagcttg tcgacttacg gatccttatc gtc 3327952DNAArtificial SequenceSynthetic sequence 27taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaaataattt 60tgtttaactt taagaaggag atatacatat ggcaggccag gcgattgcta accgcttcac 120ttctaatatc aaaggtctga ctcaggcttc ccgtaacgct aacgacggca tttctattgc 180gcagaccact gaaggtgcgc tgaatgaaat caacaacaac ctgcagcgtg tgcgtgagtt 240gtctgttcag gccactaacg ggactaactc tgattccgat ctgaaatcta tccaggatga 300aattcagcaa cgtctggaag aaatcgatcg cgtttctaat cagactcaat ttaacggtgt 360taaagtcctg tctcaggaca accagatgaa aatccaggtt ggtgctaacg atggtgaaac 420cattaccatc gatctgcaaa aaattgatgt gaaaagcctt ggccttgatg ggttcaatgt 480taattccccg ggaatttccg gtggtggtgg tggaattcta gactccatgg gtacattaat 540caatgaagac gctgccgcag ccaagaaaag taccgctaac ccactggctt caattgattc 600tgcattgtca aaagtggacg cagttcgttc ttctctgggg gcaattcaaa accgctttga 660ttcagccatt accaaccttg gcaatacggt aaccaatctg aactccgcgc gtagccgtat 720cgaagatgct gactatgcaa cggaagtttc taatatgtct aaagcgcaga ttctgcagca 780ggctggtact tccgttctgg cgcaggctaa ccaggttccg caaaacgtcc tctctttact 840ggttccgcgg ggttctcatc atcatcatca tcatggtatg gctagcatga ctggtggaca 900gcaaatgggt cgggatctgt acgacgatga cgataaggat ccgtaagtcg ac 95228285PRTArtificial SequenceSynthetic sequence 28Met Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly 1 5 10 15 Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln 20 25 30 Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val 35 40 45 Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp 50 55 60 Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp 65 70 75 80 Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln 85 90 95 Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile 100 105 110 Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly 115 120 125 Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu 130 135 140 Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys 145 150 155 160 Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val 165 170 175 Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser 180 185 190 Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg 195 200 205 Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser 210 215 220 Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala 225 230 235 240 Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro Arg Gly Ser 245 250 255 His His His His His His Gly Met Ala Ser Met Thr Gly Gly Gln Gln 260 265 270 Met Gly Arg Asp Leu Tyr Asp Asp Asp Asp Lys Asp Pro 275 280 285 29765DNAArtificial SequenceSynthetic sequence 29atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240ggaccatcag gtcaggatga aattcagcaa cgtctggaag aaatcgatcg cgtttctaat 300cagactcaat ttaacggtgt taaagtcctg tctcaggaca accagatgaa aatccaggtt 360ggtgctaacg atggtgaaac cattaccatc gatctgcaaa aaattgatgt gaaaagcctt 420ggccttgatg ggttcaatgt taattccccg ggaagtaccg ctaacccact ggcttcaatt 480gattctgcat tgtcaaaagt ggacgcagtt cgttcttctc tgggggcaat tcaaaaccgc 540tttgattcag ccattaccaa ccttggcaat acggtaacca atctgaactc cgcgcgtagc 600cgtatcgaag atgctgacta tgcaacggaa gtttctaata tgtctaaagc gcagattctg 660cagcaggctg gtacttccgt tctggcgcag gctaaccagg ttccgcaaaa cgtcctctct 720ttactggttc cgcggggttc tcatcatcat catcatcatg gttaa 76530254PRTArtificial SequenceSynthetic sequence 30Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gly Pro Ser Gly Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp 85 90 95 Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln 100 105 110 Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile 115 120 125 Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly 130 135 140 Phe Asn Val Asn Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile 145 150 155 160 Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala 165 170 175 Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val 180 185 190 Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala 195 200 205 Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly 210 215 220 Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser 225 230 235 240 Leu Leu Val Pro Arg Gly Ser His His His His His His Gly 245 250 3132DNAArtificial SequenceSynthetic sequence 31gatatacata tgagcgggtt acggatcaac ag 323229DNAArtificial SequenceSynthetic sequence 32agatctcccg gggaattaac attgaaccc 2933816DNAArtificial SequenceSynthetic sequence 33taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac tggaccatca 300ggtgaaattc agcaacgtct ggaagaaatc gatcgcgttt ctaatcagac tcaatttaac 360ggtgttaaag tcctgtctca ggacaaccag atgaaaatcc aggttggtgc taacgatggt 420gaaaccatta ccatcgatct gcaaaaaatt gatgtgaaaa gccttggcct tgatgggttc 480aatgttaatt ccccgggaag taccgctaac ccactggctt caattgattc tgcattgtca 540aaagtggacg cagttcgttc ttctctgggg gcaattcaaa accgctttga ttcagccatt 600accaaccttg gcaatacggt aaccaatctg aactccgcgc gtagccgtat cgaagatgct 660gactatgcaa cggaagtttc taatatgtct aaagcgcaga ttctgcagca ggctggtact 720tccgttctgg cgcaggctaa ccaggttccg caaaacgtcc tctctttact ggttccgcgg 780ggttctcatc atcatcatca tcatggttaa gtcgac 81634240PRTArtificial SequenceSynthetic sequence 34Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Gly Pro Ser Gly Glu Ile Gln Gln Arg Leu Glu Glu 65 70 75 80 Ile Asp Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu 85 90 95 Ser Gln Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu 100 105 110 Thr Ile Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu 115 120 125 Asp Gly Phe Asn Val Asn Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala 130 135 140 Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg Ser Ser Leu 145 150 155 160 Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn 165 170 175 Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp 180 185 190 Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile Leu Gln Gln 195 200 205 Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro Gln Asn Val 210 215 220 Leu Ser Leu Leu Val Pro Arg Gly Ser His His His His His His Gly 225 230 235 240 35275PRTArtificial SequenceSynthetic sequence 35Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met Gly 145 150 155 160 Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala Asn 165 170 175 Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg 180 185 190 Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn 195 200 205 Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu 210 215 220 Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile 225 230 235 240 Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro 245 250 255 Gln Asn Val Leu Ser Leu Leu Val Pro Arg Gly Ser His His His His 260 265 270 His His Gly 275 36828DNAArtificial SequenceSynthetic sequence 36atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aatttccggt ggtggtggtg gaattctaga ctccatgggt 480acattaatca atgaagacgc tgccgcagcc aagaaaagta ccgctaaccc actggcttca 540attgattctg cattgtcaaa agtggacgca gttcgttctt ctctgggggc aattcaaaac 600cgctttgatt cagccattac caaccttggc aatacggtaa ccaatctgaa ctccgcgcgt 660agccgtatcg aagatgctga ctatgcaacg gaagtttcta atatgtctaa agcgcagatt 720ctgcagcagg ctggtacttc cgttctggcg caggctaacc aggttccgca aaacgtcctc 780tctttactgg ttccgcgggg ttctcatcat catcatcatc atggttaa 8283741DNAArtificial SequenceSynthetic sequence 37tctagacccg ggaagtaccg ctaacccact ggcttcaatt g 413840DNAArtificial SequenceSynthetic sequence 38ccagtcatgt cgacttaacc atgatgatga tgatgatgag 403955DNAArtificial SequenceSynthetic sequence 39ctcatcatca tcatcatcat ggttaagtcg acaagcttgc ggccgcagag ctcgc 5540846DNAArtificial SequenceSynthetic sequence 40taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 84641753DNAArtificial SequenceSynthetic sequence 41atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggaagt ttctaatatg tctaaagcgc agattctgca gcaggctggt 660acttccgttc tggcgcaggc taaccaggtt ccgcaaaacg tcctctcttt actggttccg 720cggggttctc atcatcatca tcatcatggt taa 75342250PRTArtificial SequenceSynthetic sequence 42Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln

Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 431005DNAArtificial SequenceSynthetic sequence 43atggcacaag tcattaatac aaacagcctg tcgctgttga cccagaataa cctgaacaaa 60tctcagtcct cactgagttc cgctattgag cgtctgtcct ctggtctgcg tatcaacggc 120gcgaaagacg atgcggcagg ccaggcgatt gctaaccgct tcacttctaa tatcaaaggt 180ctgactcagg cttcccgtaa cgctaacgac ggcatttcta ttgcgcagac cactgaaggt 240gcgctgaatg aaatcaacaa caacctgcag cgtgtgcgtg agttgtctgt tcaggccact 300aacgggacta actctgattc cgatctgaaa tctatccagg atgaaattca gcaacgtctg 360gaagaaatcg atcgcgtttc taatcagact caatttaacg gtgttaaagt cctgtctcag 420gacaaccaga tgaaaatcca ggttggtgct aacgatggtg aaaccattac catcgatctg 480caaaaaattg atgtgaaaag ccttggcctt gatgggttca atgttaattc cccgggaatt 540tccggtggtg gtggtggaat tctagactcc atgggtacat taatcaatga agacgctgcc 600gcagccaaga aaagtaccgc taacccactg gcttcaattg attctgcatt gtcaaaagtg 660gacgcagttc gttcttctct gggggcaatt caaaaccgct ttgattcagc cattaccaac 720cttggcaata cggtaaccaa tctgaactcc gcgcgtagcc gtatcgaaga tgctgactat 780gcaacggaag tttctaatat gtctaaagcg cagattctgc agcaggctgg tacttccgtt 840ctggcgcagg ctaaccaggt tccgcaaaac gtcctctctt tactggttcc gcggggttct 900catcatcatc atcatcatgg tatggctagc atgactggtg gacagcaaat gggtcgggat 960ctgtacgacg atgacgataa ggatccgtaa gtcgacaagc ttgcg 100544329PRTArtificial SequenceSynthetic sequence 44Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn 1 5 10 15 Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg Leu 20 25 30 Ser Ser Gly Leu Arg Ile Asn Gly Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 50 55 60 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 65 70 75 80 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 85 90 95 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 100 105 110 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 115 120 125 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 130 135 140 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 145 150 155 160 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 165 170 175 Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met Gly 180 185 190 Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala Asn 195 200 205 Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg 210 215 220 Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn 225 230 235 240 Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu 245 250 255 Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile 260 265 270 Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro 275 280 285 Gln Asn Val Leu Ser Leu Leu Val Pro Arg Gly Ser His His His His 290 295 300 His His Gly Met Ala Ser Met Thr Gly Gly Gln Gln Met Gly Arg Asp 305 310 315 320 Leu Tyr Asp Asp Asp Asp Lys Asp Pro 325 4536DNAArtificial SequenceSynthetic sequence 45ctctggtcat atgatcaaca gcgcgaaaga cgatgc 364646DNAArtificial SequenceSynthetic sequence 46tctagagtcg actattaagc cataccatga tgatgatgat gatgag 4647918DNAArtificial SequenceSynthetic sequence 47taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaaataattt 60tgtttaactt taagaaggag atatacatat gatcaacagc gcgaaagacg atgcggcagg 120ccaggcgatt gctaaccgct tcacttctaa tatcaaaggt ctgactcagg cttcccgtaa 180cgctaacgac ggcatttcta ttgcgcagac cactgaaggt gcgctgaatg aaatcaacaa 240caacctgcag cgtgtgcgtg agttgtctgt tcaggccact aacgggacta actctgattc 300cgatctgaaa tctatccagg atgaaattca gcaacgtctg gaagaaatcg atcgcgtttc 360taatcagact caatttaacg gtgttaaagt cctgtctcag gacaaccaga tgaaaatcca 420ggttggtgct aacgatggtg aaaccattac catcgatctg caaaaaattg atgtgaaaag 480ccttggcctt gatgggttca atgttaattc cccgggaatt tccggtggtg gtggtggaat 540tctagactcc atgggtacat taatcaatga agacgctgcc gcagccaaga aaagtaccgc 600taacccactg gcttcaattg attctgcatt gtcaaaagtg gacgcagttc gttcttctct 660gggggcaatt caaaaccgct ttgattcagc cattaccaac cttggcaata cggtaaccaa 720tctgaactcc gcgcgtagcc gtatcgaaga tgctgactat gcaacggaag tttctaatat 780gtctaaagcg cagattctgc agcaggctgg tacttccgtt ctggcgcagg ctaaccaggt 840tccgcaaaac gtcctctctt tactggttcc gcggggttct catcatcatc atcatcatgg 900tatggcttaa tagtcgac 91848273PRTArtificial SequenceSynthetic sequence 48Met Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln Ala Ile Ala Asn 1 5 10 15 Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala Ser Arg Asn Ala 20 25 30 Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly Ala Leu Asn Glu 35 40 45 Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser Val Gln Ala Thr 50 55 60 Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile Gln Asp Glu Ile 65 70 75 80 Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn Gln Thr Gln Phe 85 90 95 Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met Lys Ile Gln Val 100 105 110 Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu Gln Lys Ile Asp 115 120 125 Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn Ser Pro Gly Ile 130 135 140 Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met Gly Thr Leu Ile Asn 145 150 155 160 Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala Asn Pro Leu Ala Ser 165 170 175 Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly 180 185 190 Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr 195 200 205 Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr 210 215 220 Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala 225 230 235 240 Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu 245 250 255 Ser Leu Leu Val Pro Arg Gly Ser His His His His His His Gly Met 260 265 270 Ala 49333PRTArtificial SequenceSynthetic sequence 49Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr 1 5 10 15 Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30 Ser Ala Lys Asp Pro Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser 35 40 45 Leu Leu Thr Gln Asn Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser 50 55 60 Ala Ile Glu Arg Leu Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp 65 70 75 80 Asp Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys 85 90 95 Gly Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala 100 105 110 Gln Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg 115 120 125 Val Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser 130 135 140 Asp Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile 145 150 155 160 Asp Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser 165 170 175 Gln Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr 180 185 190 Ile Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp 195 200 205 Gly Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile 210 215 220 Leu Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys 225 230 235 240 Lys Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys 245 250 255 Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp 260 265 270 Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala 275 280 285 Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met 290 295 300 Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln 305 310 315 320 Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Arg 325 330 501002DNAArtificial SequenceSynthetic sequence 50atgcggggtt ctcatcatca tcatcatcat ggtatggcta gcatgactgg tggacagcaa 60atgggtcggg atctgtacga cctggttccg cgcggtagcg cgaaggatcc gatggcacaa 120gtcattaata caaacagcct gtcgctgttg acccagaata acctgaacaa atctcagtcc 180tcactgagtt ccgctattga gcgtctgtcc tctggtctgc gtatcaacag cgcgaaagac 240gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 300gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 360gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 420aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 480gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 540atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 600gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaat ttccggtggt 660ggtggtggaa ttctagactc catgggtaca ttaatcaatg aagacgctgc cgcagccaag 720aaaagtaccg ctaacccact ggcttcaatt gattctgcat tgtcaaaagt ggacgcagtt 780cgttcttctc tgggggcaat tcaaaaccgt tttgattcag ccattaccaa ccttggcaat 840acggtaacca atctgaactc cgcgcgtagc cgtatcgaag atgctgacta tgcaacggaa 900gtttctaata tgtctaaagc gcagattctg cagcaggctg gtacttccgt tctggcgcag 960gctaaccagg ttccgcaaaa cgtcctctct ttactgcgtt aa 10025142DNAArtificial SequenceSynthetic sequence 51ggcaattcaa aaccgttttg attaagccat taccaacctt gg 425242DNAArtificial SequenceSynthetic sequence 52ccaaggttgg taatggctta atcaaaacgg ttttgaattg cc 4253906DNAArtificial SequenceSynthetic sequence 53taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg cggggttctc atcatcatca tcatcatggt 120atggctagca tgactggtgg acagcaaatg ggtcgggatc tgtacgacct ggttccgcgc 180ggtagcgcga aggatccgat ggcacaagtc attaatacaa acagcctgtc gctgttgacc 240cagaataacc tgaacaaatc tcagtcctca ctgagttccg ctattgagcg tctgtcctct 300ggtctgcgta tcaacagcgc gaaagacgat gcggcaggcc aggcgattgc taaccgcttc 360acttctaata tcaaaggtct gactcaggct tcccgtaacg ctaacgacgg catttctatt 420gcgcagacca ctgaaggtgc gctgaatgaa atcaacaaca acctgcagcg tgtgcgtgag 480ttgtctgttc aggccactaa cgggactaac tctgattccg atctgaaatc tatccaggat 540gaaattcagc aacgtctgga agaaatcgat cgcgtttcta atcagactca atttaacggt 600gttaaagtcc tgtctcagga caaccagatg aaaatccagg ttggtgctaa cgatggtgaa 660accattacca tcgatctgca aaaaattgat gtgaaaagcc ttggccttga tgggttcaat 720gttaattccc cgggaatttc cggtggtggt ggtggaattc tagactccat gggtacatta 780atcaatgaag acgctgccgc agccaagaaa agtaccgcta acccactggc ttcaattgat 840tctgcattgt caaaagtgga cgcagttcgt tcttctctgg gggcaattca aaaccgtttt 900gattaa 90654272PRTArtificial SequenceSynthetic sequence 54Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr 1 5 10 15 Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30 Ser Ala Lys Asp Pro Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser 35 40 45 Leu Leu Thr Gln Asn Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser 50 55 60 Ala Ile Glu Arg Leu Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp 65 70 75 80 Asp Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys 85 90 95 Gly Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala 100 105 110 Gln Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg 115 120 125 Val Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser 130 135 140 Asp Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile 145 150 155 160 Asp Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser 165 170 175 Gln Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr 180 185 190 Ile Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp 195 200 205 Gly Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile 210 215 220 Leu Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys 225 230 235 240 Lys Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys 245 250 255 Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp 260 265 270 5545DNAArtificial SequenceSynthetic sequence 55caatctgaac tccgcgcgtt gacgtatcta agatgctgac tatgc 455645DNAArtificial SequenceSynthetic sequence 56gcatagtcag catcttagat acgtcaacgc gcggagttca gattg 4557966DNAArtificial SequenceSynthetic sequence 57taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg cggggttctc atcatcatca tcatcatggt 120atggctagca tgactggtgg acagcaaatg ggtcgggatc tgtacgacct ggttccgcgc 180ggtagcgcga aggatccgat ggcacaagtc attaatacaa acagcctgtc gctgttgacc 240cagaataacc tgaacaaatc tcagtcctca ctgagttccg ctattgagcg tctgtcctct 300ggtctgcgta tcaacagcgc gaaagacgat gcggcaggcc aggcgattgc taaccgcttc 360acttctaata tcaaaggtct gactcaggct tcccgtaacg ctaacgacgg catttctatt 420gcgcagacca ctgaaggtgc gctgaatgaa atcaacaaca acctgcagcg tgtgcgtgag 480ttgtctgttc aggccactaa cgggactaac tctgattccg atctgaaatc tatccaggat 540gaaattcagc aacgtctgga agaaatcgat cgcgtttcta atcagactca atttaacggt 600gttaaagtcc tgtctcagga caaccagatg aaaatccagg ttggtgctaa cgatggtgaa 660accattacca tcgatctgca aaaaattgat gtgaaaagcc ttggccttga tgggttcaat 720gttaattccc cgggaatttc cggtggtggt ggtggaattc tagactccat gggtacatta 780atcaatgaag acgctgccgc agccaagaaa agtaccgcta acccactggc ttcaattgat 840tctgcattgt caaaagtgga cgcagttcgt tcttctctgg gggcaattca aaaccgtttt 900gattcagcca ttaccaacct tggcaatacg gtaaccaatc tgaactccgc gcgttgacgt 960atctaa 96658289PRTArtificial SequenceSynthetic sequence 58Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr 1 5 10 15 Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30 Ser Ala Lys Asp Pro Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser 35 40 45 Leu Leu Thr Gln Asn Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser 50 55 60 Ala Ile Glu Arg Leu Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp 65 70 75 80 Asp Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys 85 90 95 Gly Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala 100 105 110 Gln Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg 115 120 125 Val Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser 130 135 140 Asp Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile 145 150 155

160 Asp Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser 165 170 175 Gln Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr 180 185 190 Ile Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp 195 200 205 Gly Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile 210 215 220 Leu Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys 225 230 235 240 Lys Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys 245 250 255 Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp 260 265 270 Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala 275 280 285 Arg 5948DNAArtificial SequenceSynthetic sequence 59cgtagccgta tcgaagatgc ttaataggca acggaagttt ctaatatg 486048DNAArtificial SequenceSynthetic sequence 60catattagaa acttccgttg cctattaagc atcttcgata cggctacg 4861978DNAArtificial SequenceSynthetic sequence 61taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg cggggttctc atcatcatca tcatcatggt 120atggctagca tgactggtgg acagcaaatg ggtcgggatc tgtacgacct ggttccgcgc 180ggtagcgcga aggatccgat ggcacaagtc attaatacaa acagcctgtc gctgttgacc 240cagaataacc tgaacaaatc tcagtcctca ctgagttccg ctattgagcg tctgtcctct 300ggtctgcgta tcaacagcgc gaaagacgat gcggcaggcc aggcgattgc taaccgcttc 360acttctaata tcaaaggtct gactcaggct tcccgtaacg ctaacgacgg catttctatt 420gcgcagacca ctgaaggtgc gctgaatgaa atcaacaaca acctgcagcg tgtgcgtgag 480ttgtctgttc aggccactaa cgggactaac tctgattccg atctgaaatc tatccaggat 540gaaattcagc aacgtctgga agaaatcgat cgcgtttcta atcagactca atttaacggt 600gttaaagtcc tgtctcagga caaccagatg aaaatccagg ttggtgctaa cgatggtgaa 660accattacca tcgatctgca aaaaattgat gtgaaaagcc ttggccttga tgggttcaat 720gttaattccc cgggaatttc cggtggtggt ggtggaattc tagactccat gggtacatta 780atcaatgaag acgctgccgc agccaagaaa agtaccgcta acccactggc ttcaattgat 840tctgcattgt caaaagtgga cgcagttcgt tcttctctgg gggcaattca aaaccgtttt 900gattcagcca ttaccaacct tggcaatacg gtaaccaatc tgaactccgc gcgtagccgt 960atcgaagatg cttaatag 97862295PRTArtificial SequenceSynthetic sequence 62Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr 1 5 10 15 Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30 Ser Ala Lys Asp Pro Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser 35 40 45 Leu Leu Thr Gln Asn Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser 50 55 60 Ala Ile Glu Arg Leu Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp 65 70 75 80 Asp Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys 85 90 95 Gly Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala 100 105 110 Gln Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg 115 120 125 Val Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser 130 135 140 Asp Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile 145 150 155 160 Asp Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser 165 170 175 Gln Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr 180 185 190 Ile Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp 195 200 205 Gly Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile 210 215 220 Leu Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys 225 230 235 240 Lys Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys 245 250 255 Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp 260 265 270 Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala 275 280 285 Arg Ser Arg Ile Glu Asp Ala 290 295 63990DNAArtificial SequenceSynthetic sequence 63atgcggggtt ctcatcatca tcatcatcat ggtatggcta gcatgactgg tggacagcaa 60atgggtcggg atctgtacga cgatgacgat aaggatccga tggcacaagt cattaataca 120aacagcctgt cgctgttgac ccagaataac ctgaacaaat ctcagtcctc actgagttcc 180gctattgagc gtctgtcctc tggtctgcgt atcaacagcg cgaaagacga tgcggcaggc 240caggcgattg ctaaccgctt cacttctaat atcaaaggtc tgactcaggc ttcccgtaac 300gctaacgacg gcatttctat tgcgcagacc actgaaggtg cgctgaatga aatcaacaac 360aacctgcagc gtgtgcgtga gttgtctgtt caggccacta acgggactaa ctctgattcc 420gatctgaaat ctatccagga tgaaattcag caacgtctgg aagaaatcga tcgcgtttct 480aatcagactc aatttaacgg tgttaaagtc ctgtctcagg acaaccagat gaaaatccag 540gttggtgcta acgatggtga aaccattacc atcgatctgc aaaaaattga tgtgaaaagc 600cttggccttg atgggttcaa tgttaattcc ccgggaattt ccggtggtgg tggtggaatt 660ctagactcca tgggtacatt aatcaatgaa gacgctgccg cagccaagaa aagtaccgct 720aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 780ggggcaattc aaaaccgttt tgattcagcc attaccaacc ttggcaatac ggtaaccaat 840ctgaactccg cgcgtagccg tatcgaagat gctgactatg caacggaagt ttctaatatg 900tctaaagcgc agattctgca gcaggctggt acttccgttc tggcgcaggc taaccaggtt 960ccgcaaaacg tcctctcttt actgcgttaa 9906433DNAArtificial SequenceSynthetic sequence 64cgataaggat catatggcac aagtcattaa tac 336578DNAArtificial SequenceSynthetic sequence 65agatctgtcg acttaaccat gatgatgatg atgatgagaa ccccgcggaa ccagtgcata 60gtcagcatct tcgatacg 7866918DNAArtificial SequenceSynthetic sequence 66taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg gcacaagtca ttaatacaaa cagcctgtcg 120ctgttgaccc agaataacct gaacaaatct cagtcctcac tgagttccgc tattgagcgt 180ctgtcctctg gtctgcgtat caacagcgcg aaagacgatg cggcaggcca ggcgattgct 240aaccgcttca cttctaatat caaaggtctg actcaggctt cccgtaacgc taacgacggc 300atttctattg cgcagaccac tgaaggtgcg ctgaatgaaa tcaacaacaa cctgcagcgt 360gtgcgtgagt tgtctgttca ggccactaac gggactaact ctgattccga tctgaaatct 420atccaggatg aaattcagca acgtctggaa gaaatcgatc gcgtttctaa tcagactcaa 480tttaacggtg ttaaagtcct gtctcaggac aaccagatga aaatccaggt tggtgctaac 540gatggtgaaa ccattaccat cgatctgcaa aaaattgatg tgaaaagcct tggccttgat 600gggttcaatg ttaattcccc gggaatttcc ggtggtggtg gtggaattct agactccatg 660ggtacattaa tcaatgaaga cgctgccgca gccaagaaaa gtaccgctaa cccactggct 720tcaattgatt ctgcattgtc aaaagtggac gcagttcgtt cttctctggg ggcaattcaa 780aaccgttttg attcagccat taccaacctt ggcaatacgg taaccaatct gaactccgcg 840cgtagccgta tcgaagatgc tgactatgca ctggttccgc ggggttctca tcatcatcat 900catcatggtt aagtcgac 91867274PRTArtificial SequenceSynthetic sequence 67Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn 1 5 10 15 Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg Leu 20 25 30 Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 35 40 45 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 50 55 60 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 65 70 75 80 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 85 90 95 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 100 105 110 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 115 120 125 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 130 135 140 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 145 150 155 160 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 165 170 175 Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met Gly 180 185 190 Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala Asn 195 200 205 Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg 210 215 220 Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn 225 230 235 240 Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu 245 250 255 Asp Ala Asp Tyr Ala Leu Val Pro Arg Gly Ser His His His His His 260 265 270 His Gly 6840DNAArtificial SequenceSynthetic sequence 68agatctccgc ggaaccagac cagcctgctg cagaatctgc 4069795DNAArtificial SequenceSynthetic sequence 69taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtctg gttccgcggg gttctcatca tcatcatcat 780catggttaag tcgac 79570702DNAArtificial SequenceSynthetic sequence 70atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggaagt ttctaatatg tctaaagcgc agattctgca gcaggctggt 660ctggttccgc ggggttctca tcatcatcat catcatggtt aa 70271233PRTArtificial SequenceSynthetic sequence 71Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Leu Val Pro Arg 210 215 220 Gly Ser His His His His His His Gly 225 230 72120DNAArtificial SequenceSynthetic sequence 72aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 60ggggcaattc aaaaccgttt tgattcagcc attaccgccc ttggcaatac ggtaaccaat 1207340PRTArtificial SequenceSynthetic sequence 73Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val 1 5 10 15 Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr 20 25 30 Ala Leu Gly Asn Thr Val Thr Asn 35 40 7446DNAArtificial SequenceSynthetic sequence 74gttcgttctt ctctgggggc aattgattca gccattaccg cccttg 467546DNAArtificial SequenceSynthetic sequence 75caagggcggt aatggctgaa tcaattgccc ccagagaaga acgaac 4676783DNAArtificial SequenceSynthetic sequence 76taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattgatt cagccattac cgcccttggc aatacggtaa ccaatctgaa ctccgcgcgt 660agccgtatcg aagatgctga ctatgcaacg gaagtttcta atatgtctaa agcgcagatt 720ctgcagcagg ctggtctggt tccgcggggt tctcatcatc atcatcatca tggttaagtc 780gac 78377229PRTArtificial SequenceSynthetic sequence 77Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Asp Ser Ala 165 170 175 Ile Thr Ala Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser 180 185 190 Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys 195 200 205 Ala Gln Ile Leu Gln Gln Ala Gly Leu Val Pro Arg Gly Ser His His 210 215 220 His His His His Gly 225 78654DNAArtificial SequenceSynthetic sequence 78atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg

420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg cactggttcc gcggggttct catcatcatc atcatcatgg ttaa 65479217PRTArtificial SequenceSynthetic sequence 79Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Leu Val Pro Arg 195 200 205 Gly Ser His His His His His His Gly 210 215 80714DNAArtificial SequenceSynthetic sequence 80atgagtaaag gagaagaact tttcactgga gttgtcccaa ttcttgttga attagatggt 60gatgttaatg ggcacaaatt ttctgtcagt ggagagggtg aaggtgatgc aacatacgga 120aaacttaccc ttaaatttat ttgcactact ggaaaactac ctgttccatg gccaacactt 180gtcactactc tgacgtatgg tgttcaatgc ttttcccgtt atccggatca tatgaaacgg 240catgactttt tcaagagtgc catgcccgaa ggttatgtac aggaacgcac tatatctttc 300aaagatgacg ggaactacaa gacgcgtgct gaagtcaagt ttgaaggtga tacccttgtt 360aatcgtatcg agttaaaagg tattgatttt aaagaagatg gaaacattct cggacacaaa 420ctcgagtaca actataactc acacaatgta tacatcacgg cagacaaaca aaagaatgga 480atcaaagcta acttcaaaat tcgccacaac attgaagatg gatccgttca actagcagac 540cattatcaac aaaatactcc aattggcgat ggccctgtcc ttttaccaga caaccattac 600ctgtcgacac aatctgccct tttgaaagat cccaacgaaa agcgtgacca catggtcctt 660cttgagtttg taactgctgc tgggattaca catggcatgg atgaactata caaa 71481238PRTArtificial SequenceSynthetic sequence 81Met Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu Val 1 5 10 15 Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly Glu 20 25 30 Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile Cys 35 40 45 Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr Leu 50 55 60 Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp His Met Lys Arg 65 70 75 80 His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gln Glu Arg 85 90 95 Thr Ile Ser Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val 100 105 110 Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly Ile 115 120 125 Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr Asn 130 135 140 Tyr Asn Ser His Asn Val Tyr Ile Thr Ala Asp Lys Gln Lys Asn Gly 145 150 155 160 Ile Lys Ala Asn Phe Lys Ile Arg His Asn Ile Glu Asp Gly Ser Val 165 170 175 Gln Leu Ala Asp His Tyr Gln Gln Asn Thr Pro Ile Gly Asp Gly Pro 180 185 190 Val Leu Leu Pro Asp Asn His Tyr Leu Ser Thr Gln Ser Ala Leu Leu 195 200 205 Lys Asp Pro Asn Glu Lys Arg Asp His Met Val Leu Leu Glu Phe Val 210 215 220 Thr Ala Ala Gly Ile Thr His Gly Met Asp Glu Leu Tyr Lys 225 230 235 82717DNAArtificial SequenceSynthetic sequence 82atgagtaaag gagaagaact tttcactgga gttgtcccaa ttcttgttga attagatggt 60gatgttaatg ggcacaaatt ttctgtcagt ggagagggtg aaggtgatgc aacatacgga 120aaacttaccc ttaaatttat ttgcactact ggaaaactac ctgttccatg gccaacactt 180gtcactactc tgacgtatgg tgttcaatgc ttttcccgtt atccggatca catgaaacgg 240catgactttt tcaagagtgc catgcccgaa ggttatgtac aggaacgcac tatatctttc 300aaagatgacg ggaactacaa gacgcgtgct gaagtcaagt ttgaaggtga tacccttgtt 360aatcgtatcg agttaaaagg tattgatttt aaagaagatg gaaacattct cggacacaaa 420ctcgagtaca actataactc acacaatgta tacatcacgg cagacaaaca aaagaatgga 480atcaaagcta acttcaaaat tcgccacaac attgaagatg gatccgttca actagcagac 540cattatcaac aaaatactcc aattggcgat ggccctgtcc ttttaccaga caaccattac 600ctgtcgacac aatctgccct tttgaaagat cccaacgaaa agcgtgacca catggtcctt 660cttgagtttg taactgctgc tgggattaca catggcatgg atgaactata caaataa 7178354DNAArtificial SequenceSynthetic sequence 83tctagacggc cgatctcagg taagaatgga atcaaagcta acttcaaaat tcgc 548420PRTArtificial SequenceSynthetic sequence 84Asn Val Tyr Ile Pro Ile Ser Gly Lys Asn Gly Ile Lys Ala Asn Phe 1 5 10 15 Lys Ile Arg His 20 8545DNAArtificial SequenceSynthetic sequence 85agatctccgc ggtttgtata gttcatccat gccatgtgta atccc 45861005DNAArtificial SequenceSynthetic sequence 86taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcac tggttccgcc gatctcaggt 720aagaatggaa tcaaagctaa cttcaaaatt cgccacaaca ttgaagatgg atccgttcaa 780ctagcagacc attatcaaca aaatactcca attggcgatg gccctgtcct tttaccagac 840aaccattacc tgtcgacaca atctgccctt ttgaaagatc ccaacgaaaa gcgtgaccac 900atggtccttc ttgagtttgt aactgctgct gggattacac atggcatgga tgaactatac 960aaaccgcggg gttctcatca tcatcatcat catggttaag tcgac 100587912DNAArtificial SequenceSynthetic sequence 87atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg cactggttcc gccgatctca ggtaagaatg gaatcaaagc taacttcaaa 660attcgccaca acattgaaga tggatccgtt caactagcag accattatca acaaaatact 720ccaattggcg atggccctgt ccttttacca gacaaccatt acctgtcgac acaatctgcc 780cttttgaaag atcccaacga aaagcgtgac cacatggtcc ttcttgagtt tgtaactgct 840gctgggatta cacatggcat ggatgaacta tacaaaccgc ggggttctca tcatcatcat 900catcatggtt aa 91288303PRTArtificial SequenceSynthetic sequence 88Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Leu Val Pro Pro 195 200 205 Ile Ser Gly Lys Asn Gly Ile Lys Ala Asn Phe Lys Ile Arg His Asn 210 215 220 Ile Glu Asp Gly Ser Val Gln Leu Ala Asp His Tyr Gln Gln Asn Thr 225 230 235 240 Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His Tyr Leu Ser 245 250 255 Thr Gln Ser Ala Leu Leu Lys Asp Pro Asn Glu Lys Arg Asp His Met 260 265 270 Val Leu Leu Glu Phe Val Thr Ala Ala Gly Ile Thr His Gly Met Asp 275 280 285 Glu Leu Tyr Lys Pro Arg Gly Ser His His His His His His Gly 290 295 300 89585DNAArtificial SequenceSynthetic sequence 89atgagtaccg ctaacccact ggcttcaatt gattctgcat tgtcaaaagt ggacgcagtt 60cgttcttctc tgggggcaat tcaaaaccgc tttgattcag ccattaccaa ccttggcaat 120acggtaacca atctgaactc cgcgcgtagc cgtatcgaag atgctgacta tgcatccccg 180ggaagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 240cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 300tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 360cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 420caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 480aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 540ggtctggttc cgcggggttc tcatcatcat catcatcatg gttaa 58590194PRTArtificial SequenceSynthetic sequence 90Met Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys 1 5 10 15 Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp 20 25 30 Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala 35 40 45 Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Ser Pro Gly Ser Gly Leu 50 55 60 Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln Ala Ile Ala Asn 65 70 75 80 Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala Ser Arg Asn Ala 85 90 95 Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly Ala Leu Asn Glu 100 105 110 Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser Val Gln Ala Thr 115 120 125 Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile Gln Asp Glu Ile 130 135 140 Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn Gln Thr Gln Phe 145 150 155 160 Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met Lys Ile Gln Val 165 170 175 Gly Ala Asn Asp Gly Leu Val Pro Arg Gly Ser His His His His His 180 185 190 His Gly 91678DNAArtificial SequenceSynthetic sequence 91taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agtaccgcta acccactggc ttcaattgat 120tctgcattgt caaaagtgga cgcagttcgt tcttctctgg gggcaattca aaaccgcttt 180gattcagcca ttaccaacct tggcaatacg gtaaccaatc tgaactccgc gcgtagccgt 240atcgaagatg ctgactatgc atccccggga agcgggttac ggatcaacag cgcgaaagac 300gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 360gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 420gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 480aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 540gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 600atgaaaatcc aggttggtgc taacgatggt ctggttccgc ggggttctca tcatcatcat 660catcatggtt aagtcgac 6789240DNAArtificial SequenceSynthetic sequence 92tctagacata tgagtaccgc taacccactg gcttcaattg 409338DNAArtificial SequenceSynthetic sequence 93gcttcccggg gatgcatagt cagcatcttc gatacggc 389434DNAArtificial SequenceSynthetic sequence 94gcatccccgg gaagcgggtt acggatcaac agcg 349550DNAArtificial SequenceSynthetic sequence 95agatctccgc ggaaccagac catcgttagc accaacctgg attttcatct 5096654DNAArtificial SequenceSynthetic sequence 96atgagtaccg ctaacccact ggcttcaatt gattctgcat tgtcaaaagt ggacgcagtt 60cgttcttctc tgggggcaat tcaaaaccgc tttgattcag ccattaccaa ccttggcaat 120acggtaacca atctgaactc cgcgcgtagc cgtatcgaag atgctgacta tgcatccccg 180ggaagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 240cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 300tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 360cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 420caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 480aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 540ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 600ttcaatgtta atctggttcc gcggggttct catcatcatc atcatcatgg ttaa 65497217PRTArtificial SequenceSynthetic sequence 97Met Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys 1 5 10 15 Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp 20 25 30 Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala 35 40 45 Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Ser Pro Gly Ser Gly Leu 50 55 60 Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln Ala Ile Ala Asn 65 70 75 80 Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala Ser Arg Asn Ala 85 90 95 Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly Ala Leu Asn Glu 100 105 110 Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser Val Gln Ala Thr 115 120 125 Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile Gln Asp Glu Ile 130 135 140 Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn Gln Thr Gln Phe 145 150 155 160 Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met Lys Ile Gln Val 165 170 175 Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu Gln Lys Ile Asp 180 185 190 Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn Leu Val Pro Arg 195 200 205 Gly Ser His His His His His His Gly 210 215 98747DNAArtificial SequenceSynthetic sequence 98taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agtaccgcta acccactggc ttcaattgat 120tctgcattgt caaaagtgga cgcagttcgt tcttctctgg gggcaattca aaaccgcttt 180gattcagcca ttaccaacct tggcaatacg gtaaccaatc tgaactccgc gcgtagccgt 240atcgaagatg ctgactatgc atccccggga agcgggttac ggatcaacag cgcgaaagac 300gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 360gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 420gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact

480aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 540gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 600atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 660gatgtgaaaa gccttggcct tgatgggttc aatgttaatc tggttccgcg gggttctcat 720catcatcatc atcatggtta agtcgac 7479945DNAArtificial SequenceSynthetic sequence 99agatctccgc ggaaccagat taacattgaa cccatcaagg ccaag 4510038DNAArtificial SequenceSynthetic sequence 100cccgttatcc ggatcacatg aaacggcatg actttttc 3810138DNAArtificial SequenceSynthetic sequence 101gaaaaagtca tgccgtttca tgtgatccgg ataacggg 3810221DNAArtificial SequenceSynthetic sequence 102ctgttccatg gccaacactt g 2110346DNAArtificial SequenceSynthetic sequence 103tctagacata tgagtaaagg agaagaactt ttcactggag ttgtcc 4610463DNAArtificial SequenceSynthetic sequence 104ggcctatgcg gccgcagtaa aggagaagaa cttttcactg gagttgtccc aattcttgtt 60gaa 6310557DNAArtificial SequenceSynthetic sequence 105agatctatta atgcggcctg ataggccttg tttgtctgcc gtgatgtata cattgtg 5710618PRTArtificial SequenceSynthetic sequence 106Ser His Asn Val Tyr Ile Thr Ala Asp Lys Gln Gly Leu Ser Gly Arg 1 5 10 15 Asn Met 1071494DNAArtificial SequenceSynthetic sequence 107taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agtaaaggag aagaactttt cactggagtt 120gtcccaattc ttgttgaatt agatggtgat gttaatgggc acaaattttc tgtcagtgga 180gagggtgaag gtgatgcaac atacggaaaa cttaccctta aatttatttg cactactgga 240aaactacctg ttccatggcc aacacttgtc actactctga cgtatggtgt tcaatgcttt 300tcccgttatc cggatcacat gaaacggcat gactttttca agagtgccat gcccgaaggt 360tatgtacagg aacgcactat atctttcaaa gatgacggga actacaagac gcgtgctgaa 420gtcaagtttg aaggtgatac ccttgttaat cgtatcgagt taaaaggtat tgattttaaa 480gaagatggaa acattctcgg acacaaactc gagtacaact ataactcaca caatgtatac 540atcacggcag acaaacaagg cctatcaggc cgcattatga gcgggttacg gatcaacagc 600gcgaaagacg atgcggcagg ccaggcgatt gctaaccgct tcacttctaa tatcaaaggt 660ctgactcagg cttcccgtaa cgctaacgac ggcatttcta ttgcgcagac cactgaaggt 720gcgctgaatg aaatcaacaa caacctgcag cgtgtgcgtg agttgtctgt tcaggccact 780aacgggacta actctgattc cgatctgaaa tctatccagg atgaaattca gcaacgtctg 840gaagaaatcg atcgcgtttc taatcagact caatttaacg gtgttaaagt cctgtctcag 900gacaaccaga tgaaaatcca ggttggtgct aacgatggtg aaaccattac catcgatctg 960caaaaaattg atgtgaaaag ccttggcctt gatgggttca atgttaattc cccgggaagt 1020accgctaacc cactggcttc aattgattct gcattgtcaa aagtggacgc agttcgttct 1080tctctggggg caattcaaaa ccgctttgat tcagccatta ccaaccttgg caatacggta 1140accaatctga actccgcgcg tagccgtatc gaagatgctg actatgcact ggttccgccg 1200atctcaggta agaatggaat caaagctaac ttcaaaattc gccacaacat tgaagatgga 1260tccgttcaac tagcagacca ttatcaacaa aatactccaa ttggcgatgg ccctgtcctt 1320ttaccagaca accattacct gtcgacacaa tctgcccttt tgaaagatcc caacgaaaag 1380cgtgaccaca tggtccttct tgagtttgta actgctgctg ggattacaca tggcatggat 1440gaactataca aaccgcgggg ttctcatcat catcatcatc atggttaagt cgac 14941081401DNAArtificial SequenceSynthetic sequence 108atgagtaaag gagaagaact tttcactgga gttgtcccaa ttcttgttga attagatggt 60gatgttaatg ggcacaaatt ttctgtcagt ggagagggtg aaggtgatgc aacatacgga 120aaacttaccc ttaaatttat ttgcactact ggaaaactac ctgttccatg gccaacactt 180gtcactactc tgacgtatgg tgttcaatgc ttttcccgtt atccggatca catgaaacgg 240catgactttt tcaagagtgc catgcccgaa ggttatgtac aggaacgcac tatatctttc 300aaagatgacg ggaactacaa gacgcgtgct gaagtcaagt ttgaaggtga tacccttgtt 360aatcgtatcg agttaaaagg tattgatttt aaagaagatg gaaacattct cggacacaaa 420ctcgagtaca actataactc acacaatgta tacatcacgg cagacaaaca aggcctatca 480ggccgcatta tgagcgggtt acggatcaac agcgcgaaag acgatgcggc aggccaggcg 540attgctaacc gcttcacttc taatatcaaa ggtctgactc aggcttcccg taacgctaac 600gacggcattt ctattgcgca gaccactgaa ggtgcgctga atgaaatcaa caacaacctg 660cagcgtgtgc gtgagttgtc tgttcaggcc actaacggga ctaactctga ttccgatctg 720aaatctatcc aggatgaaat tcagcaacgt ctggaagaaa tcgatcgcgt ttctaatcag 780actcaattta acggtgttaa agtcctgtct caggacaacc agatgaaaat ccaggttggt 840gctaacgatg gtgaaaccat taccatcgat ctgcaaaaaa ttgatgtgaa aagccttggc 900cttgatgggt tcaatgttaa ttccccggga agtaccgcta acccactggc ttcaattgat 960tctgcattgt caaaagtgga cgcagttcgt tcttctctgg gggcaattca aaaccgcttt 1020gattcagcca ttaccaacct tggcaatacg gtaaccaatc tgaactccgc gcgtagccgt 1080atcgaagatg ctgactatgc actggttccg ccgatctcag gtaagaatgg aatcaaagct 1140aacttcaaaa ttcgccacaa cattgaagat ggatccgttc aactagcaga ccattatcaa 1200caaaatactc caattggcga tggccctgtc cttttaccag acaaccatta cctgtcgaca 1260caatctgccc ttttgaaaga tcccaacgaa aagcgtgacc acatggtcct tcttgagttt 1320gtaactgctg ctgggattac acatggcatg gatgaactat acaaaccgcg gggttctcat 1380catcatcatc atcatggtta a 1401109466PRTArtificial SequenceSynthetic sequence 109Met Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu Val 1 5 10 15 Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly Glu 20 25 30 Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile Cys 35 40 45 Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr Leu 50 55 60 Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp His Met Lys Arg 65 70 75 80 His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gln Glu Arg 85 90 95 Thr Ile Ser Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val 100 105 110 Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly Ile 115 120 125 Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr Asn 130 135 140 Tyr Asn Ser His Asn Val Tyr Ile Thr Ala Asp Lys Gln Gly Leu Ser 145 150 155 160 Gly Arg Ile Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala 165 170 175 Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu 180 185 190 Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr 195 200 205 Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg 210 215 220 Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu 225 230 235 240 Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg 245 250 255 Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp 260 265 270 Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr 275 280 285 Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe 290 295 300 Asn Val Asn Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp 305 310 315 320 Ser Ala Leu Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile 325 330 335 Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr 340 345 350 Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Leu 355 360 365 Val Pro Pro Ile Ser Gly Lys Asn Gly Ile Lys Ala Asn Phe Lys Ile 370 375 380 Arg His Asn Ile Glu Asp Gly Ser Val Gln Leu Ala Asp His Tyr Gln 385 390 395 400 Gln Asn Thr Pro Ile Gly Asp Gly Pro Val Leu Leu Pro Asp Asn His 405 410 415 Tyr Leu Ser Thr Gln Ser Ala Leu Leu Lys Asp Pro Asn Glu Lys Arg 420 425 430 Asp His Met Val Leu Leu Glu Phe Val Thr Ala Ala Gly Ile Thr His 435 440 445 Gly Met Asp Glu Leu Tyr Lys Pro Arg Gly Ser His His His His His 450 455 460 His Gly 465 110124DNAArtificial SequenceSynthetic sequence 110cttggccttg atgggttcaa tgttaattcc ccgggaattt ccggtggtgg tggtggaatt 60acattaatca atgaagacgc tgccgcagcc aagaaaagta ccgctaaccc actggcttca 120attg 12411141PRTArtificial SequenceSynthetic sequence 111Leu Gly Leu Asp Gly Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly 1 5 10 15 Gly Gly Gly Ile Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys 20 25 30 Ser Thr Ala Asn Pro Leu Ala Ser Ile 35 40 11272DNAArtificial SequenceSynthetic sequence 112agatctccgc ggaaccagta aagagaggac gttttgcgga acctggtttg catagtcagc 60atcttcgata cg 72113777DNAArtificial SequenceSynthetic sequence 113taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgttttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa accaggttcc gcaaaacgtc 720ctctctttac tggttccgcg gggttctcat catcatcatc atcatggtta agtcgac 777114684DNAArtificial SequenceSynthetic sequence 114atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgttt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caaaccaggt tccgcaaaac gtcctctctt tactggttcc gcggggttct 660catcatcatc atcatcatgg ttaa 684115227PRTArtificial SequenceSynthetic sequence 115Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Asn Gln Val Pro 195 200 205 Gln Asn Val Leu Ser Leu Leu Val Pro Arg Gly Ser His His His His 210 215 220 His His Gly 225 11642DNAArtificial SequenceSynthetic sequence 116agatctcccg gggaaccatc gttagcacca acctggattt tc 42117777DNAArtificial SequenceSynthetic sequence 117taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt tccccgggaa gtaccgctaa cccactggct 480tcaattgatt ctgcattgtc aaaagtggac gcagttcgtt cttctctggg ggcaattcaa 540aaccgctttg attcagccat taccaacctt ggcaatacgg taaccaatct gaactccgcg 600cgtagccgta tcgaagatgc tgactatgca acggaagttt ctaatatgtc taaagcgcag 660attctgcagc aggctggtac ttccgttctg gcgcaggcta accaggttcc gcaaaacgtc 720ctctctttac tggttccgcg gggttctcat catcatcatc atcatggtta agtcgac 777118684DNAArtificial SequenceSynthetic sequence 118atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggttccccgg gaagtaccgc taacccactg gcttcaattg attctgcatt gtcaaaagtg 420gacgcagttc gttcttctct gggggcaatt caaaaccgct ttgattcagc cattaccaac 480cttggcaata cggtaaccaa tctgaactcc gcgcgtagcc gtatcgaaga tgctgactat 540gcaacggaag tttctaatat gtctaaagcg cagattctgc agcaggctgg tacttccgtt 600ctggcgcagg ctaaccaggt tccgcaaaac gtcctctctt tactggttcc gcggggttct 660catcatcatc atcatcatgg ttaa 684119227PRTArtificial SequenceSynthetic sequence 119Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Ser Pro Gly Ser Thr Ala Asn 115 120 125 Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val Arg 130 135 140 Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn 145 150 155 160 Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu 165 170 175 Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile 180 185 190 Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro 195 200 205 Gln Asn Val Leu Ser Leu Leu Val Pro Arg Gly Ser His His His His 210 215 220 His His Gly 225 12090DNAArtificial SequenceSynthetic sequence 120agatctccgc ggaaccagca ggttattctg ggtcaacagc gacaggctgt ttgtattaat 60gacttgtgca tagtcagcat cttcgatacg 90121795DNAArtificial SequenceSynthetic sequence 121taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct

tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcac aagtcattaa tacaaacagc 720ctgtcgctgt tgacccagaa taacctgctg gttccgcggg gttctcatca tcatcatcat 780catggttaag tcgac 795122702DNAArtificial SequenceSynthetic sequence 122atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg cacaagtcat taatacaaac agcctgtcgc tgttgaccca gaataacctg 660ctggttccgc ggggttctca tcatcatcat catcatggtt aa 702123233PRTArtificial SequenceSynthetic sequence 123Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Gln Val Ile Asn 195 200 205 Thr Asn Ser Leu Ser Leu Leu Thr Gln Asn Asn Leu Leu Val Pro Arg 210 215 220 Gly Ser His His His His His His Gly 225 230 12449DNAArtificial SequenceSynthetic sequence 124gctgactatg caacggcagt ttctgctatg tctgcagcgc agattctgc 4912549DNAArtificial SequenceSynthetic sequence 125gcagaatctg cgctgcagac atagcagaaa ctgccgttgc atagtcagc 49126795DNAArtificial SequenceSynthetic sequence 126taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggcagtttc tgctatgtct 720gcagcgcaga ttctgcagca ggctggtctg gttccgcggg gttctcatca tcatcatcat 780catggttaag tcgac 795127702DNAArtificial SequenceSynthetic sequence 127atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggcagt ttctgctatg tctgcagcgc agattctgca gcaggctggt 660ctggttccgc ggggttctca tcatcatcat catcatggtt aa 702128233PRTArtificial SequenceSynthetic sequence 128Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Ala Val Ser 195 200 205 Ala Met Ser Ala Ala Gln Ile Leu Gln Gln Ala Gly Leu Val Pro Arg 210 215 220 Gly Ser His His His His His His Gly 225 230 12954DNAArtificial SequenceSynthetic sequence 129gtttctaata tgtctaaagc ggcgattctg ggagcggctg gtctggttcc gcgg 5413054DNAArtificial SequenceSynthetic sequence 130ccgcggaacc agaccagccg ctcccagaat cgccgcttta gacatattag aaac 54131795DNAArtificial SequenceSynthetic sequence 131taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcggcga ttctgggagc ggctggtctg gttccgcggg gttctcatca tcatcatcat 780catggttaag tcgac 795132702DNAArtificial SequenceSynthetic sequence 132atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggaagt ttctaatatg tctaaagcgg cgattctggg agcggctggt 660ctggttccgc ggggttctca tcatcatcat catcatggtt aa 702133233PRTArtificial SequenceSynthetic sequence 133Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Ala Ile Leu Gly Ala Ala Gly Leu Val Pro Arg 210 215 220 Gly Ser His His His His His His Gly 225 230 13425DNAArtificial SequenceSynthetic sequence 134tctagaggat ccggcaggcc aggcg 2513522DNAArtificial SequenceSynthetic sequence 135cgcaagcttg tcgacttaac gc 22136970DNAArtificial SequenceSynthetic sequence 136taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg cggggttctc atcatcatca tcatcatggt 120atggctagca tgactggtgg acagcaaatg ggtcgggatc tgtacgacct ggttccgcgc 180ggtagcgcga aggatccggc aggccaggcg attgctaacc gcttcacttc taatatcaaa 240ggtctgactc aggcttcccg taacgctaac gacggcattt ctattgcgca gaccactgaa 300ggtgcgctga atgaaatcaa caacaacctg cagcgtgtgc gtgagttgtc tgttcaggcc 360actaacggga ctaactctga ttccgatctg aaatctatcc aggatgaaat tcagcaacgt 420ctggaagaaa tcgatcgcgt ttctaatcag actcaattta acggtgttaa agtcctgtct 480caggacaacc agatgaaaat ccaggttggt gctaacgatg gtgaaaccat taccatcgat 540ctgcaaaaaa ttgatgtgaa aagccttggc cttgatgggt tcaatgttaa ttccccggga 600atttccggtg gtggtggtgg aattctagac tccatgggta cattaatcaa tgaagacgct 660gccgcagcca agaaaagtac cgctaaccca ctggcttcaa ttgattctgc attgtcaaaa 720gtggacgcag ttcgttcttc tctgggggca attcaaaacc gttttgattc agccattacc 780aaccttggca atacggtaac caatctgaac tccgcgcgta gccgtatcga agatgctgac 840tatgcaacgg aagtttctaa tatgtctaaa gcgcagattc tgcagcaggc tggtacttcc 900gttctggcgc aggctaacca ggttccgcaa aacgtcctct ctttactgcg ttaagtcgac 960aagcttgcgg 970137288PRTArtificial SequenceSynthetic sequence 137Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr 1 5 10 15 Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30 Ser Ala Lys Asp Pro Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser 35 40 45 Asn Ile Lys Gly Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile 50 55 60 Ser Ile Ala Gln Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn 65 70 75 80 Leu Gln Arg Val Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn 85 90 95 Ser Asp Ser Asp Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu 100 105 110 Glu Glu Ile Asp Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys 115 120 125 Val Leu Ser Gln Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp 130 135 140 Gly Glu Thr Ile Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu 145 150 155 160 Gly Leu Asp Gly Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly 165 170 175 Gly Gly Ile Leu Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala 180 185 190 Ala Ala Lys Lys Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala 195 200 205 Leu Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn 210 215 220 Arg Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu 225 230 235 240 Asn Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val 245 250 255 Ser Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val 260 265 270 Leu Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Arg 275 280 285 1381236DNAArtificial SequenceSynthetic sequence 138taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agtaaaggag aagaactttt cactggagtt 120gtcccaattc ttgttgaatt agatggtgat gttaatgggc acaaattttc tgtcagtgga 180gagggtgaag gtgatgcaac atacggaaaa cttaccctta aatttatttg cactactgga 240aaactacctg ttccatggcc aacacttgtc actactctga cgtatggtgt tcaatgcttt 300tcccgttatc cggatcacat gaaacggcat gactttttca agagtgccat gcccgaaggt 360tatgtacagg aacgcactat atctttcaaa gatgacggga actacaagac gcgtgctgaa 420gtcaagtttg aaggtgatac ccttgttaat cgtatcgagt taaaaggtat tgattttaaa 480gaagatggaa acattctcgg acacaaactc gagtacaact ataactcaca caatgtatac 540atcacggcag acaaacaagg cctatcaggc cgcattatga gcgggttacg gatcaacagc 600gcgaaagacg atgcggcagg ccaggcgatt gctaaccgct tcacttctaa tatcaaaggt 660ctgactcagg cttcccgtaa cgctaacgac ggcatttcta ttgcgcagac cactgaaggt 720gcgctgaatg aaatcaacaa caacctgcag cgtgtgcgtg agttgtctgt tcaggccact 780aacgggacta actctgattc cgatctgaaa tctatccagg atgaaattca gcaacgtctg 840gaagaaatcg atcgcgtttc taatcagact caatttaacg gtgttaaagt cctgtctcag 900gacaaccaga tgaaaatcca ggttggtgct aacgatggtg aaaccattac catcgatctg 960caaaaaattg atgtgaaaag ccttggcctt gatgggttca atgttaattc cccgggaagt 1020accgctaacc cactggcttc aattgattct gcattgtcaa aagtggacgc agttcgttct 1080tctctggggg caattcaaaa ccgctttgat tcagccatta ccaaccttgg caatacggta 1140accaatctga actccgcgcg tagccgtatc gaagatgctg actatgcact ggttccgcgg 1200ggttctcatc atcatcatca tcatggttaa gtcgac 12361391143DNAArtificial SequenceSynthetic sequence 139atgagtaaag gagaagaact tttcactgga gttgtcccaa ttcttgttga attagatggt 60gatgttaatg ggcacaaatt ttctgtcagt ggagagggtg aaggtgatgc aacatacgga 120aaacttaccc ttaaatttat ttgcactact ggaaaactac ctgttccatg gccaacactt 180gtcactactc tgacgtatgg tgttcaatgc ttttcccgtt atccggatca catgaaacgg 240catgactttt tcaagagtgc catgcccgaa ggttatgtac aggaacgcac tatatctttc 300aaagatgacg ggaactacaa gacgcgtgct gaagtcaagt ttgaaggtga tacccttgtt 360aatcgtatcg agttaaaagg tattgatttt aaagaagatg gaaacattct cggacacaaa 420ctcgagtaca actataactc acacaatgta tacatcacgg cagacaaaca aggcctatca 480ggccgcatta tgagcgggtt acggatcaac agcgcgaaag acgatgcggc aggccaggcg 540attgctaacc gcttcacttc taatatcaaa ggtctgactc aggcttcccg taacgctaac 600gacggcattt ctattgcgca gaccactgaa ggtgcgctga atgaaatcaa caacaacctg 660cagcgtgtgc gtgagttgtc tgttcaggcc actaacggga ctaactctga ttccgatctg 720aaatctatcc aggatgaaat tcagcaacgt ctggaagaaa tcgatcgcgt ttctaatcag 780actcaattta acggtgttaa agtcctgtct caggacaacc agatgaaaat ccaggttggt 840gctaacgatg gtgaaaccat taccatcgat ctgcaaaaaa ttgatgtgaa aagccttggc 900cttgatgggt tcaatgttaa ttccccggga agtaccgcta acccactggc ttcaattgat 960tctgcattgt caaaagtgga cgcagttcgt tcttctctgg gggcaattca aaaccgcttt

1020gattcagcca ttaccaacct tggcaatacg gtaaccaatc tgaactccgc gcgtagccgt 1080atcgaagatg ctgactatgc actggttccg cggggttctc atcatcatca tcatcatggt 1140taa 1143140380PRTArtificial SequenceSynthetic sequence 140Met Ser Lys Gly Glu Glu Leu Phe Thr Gly Val Val Pro Ile Leu Val 1 5 10 15 Glu Leu Asp Gly Asp Val Asn Gly His Lys Phe Ser Val Ser Gly Glu 20 25 30 Gly Glu Gly Asp Ala Thr Tyr Gly Lys Leu Thr Leu Lys Phe Ile Cys 35 40 45 Thr Thr Gly Lys Leu Pro Val Pro Trp Pro Thr Leu Val Thr Thr Leu 50 55 60 Thr Tyr Gly Val Gln Cys Phe Ser Arg Tyr Pro Asp His Met Lys Arg 65 70 75 80 His Asp Phe Phe Lys Ser Ala Met Pro Glu Gly Tyr Val Gln Glu Arg 85 90 95 Thr Ile Ser Phe Lys Asp Asp Gly Asn Tyr Lys Thr Arg Ala Glu Val 100 105 110 Lys Phe Glu Gly Asp Thr Leu Val Asn Arg Ile Glu Leu Lys Gly Ile 115 120 125 Asp Phe Lys Glu Asp Gly Asn Ile Leu Gly His Lys Leu Glu Tyr Asn 130 135 140 Tyr Asn Ser His Asn Val Tyr Ile Thr Ala Asp Lys Gln Gly Leu Ser 145 150 155 160 Gly Arg Ile Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala 165 170 175 Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu 180 185 190 Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr 195 200 205 Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg 210 215 220 Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu 225 230 235 240 Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg 245 250 255 Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp 260 265 270 Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr 275 280 285 Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe 290 295 300 Asn Val Asn Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp 305 310 315 320 Ser Ala Leu Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile 325 330 335 Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr 340 345 350 Asn Leu Asn Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Leu 355 360 365 Val Pro Arg Gly Ser His His His His His His Gly 370 375 380 14136DNAArtificial SequenceSynthetic sequence 141tctagaggat ccgtctggtc tgcgtatcaa cagcgc 36142996DNAArtificial SequenceSynthetic sequence 142taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg cggggttctc atcatcatca tcatcatggt 120atggctagca tgactggtgg acagcaaatg ggtcgggatc tgtacgacct ggttccgcgc 180ggtagcgcga aggatccgtc tggtctgcgt atcaacagcg cgaaagacga tgcggcaggc 240caggcgattg ctaaccgctt cacttctaat atcaaaggtc tgactcaggc ttcccgtaac 300gctaacgacg gcatttctat tgcgcagacc actgaaggtg cgctgaatga aatcaacaac 360aacctgcagc gtgtgcgtga gttgtctgtt caggccacta acgggactaa ctctgattcc 420gatctgaaat ctatccagga tgaaattcag caacgtctgg aagaaatcga tcgcgtttct 480aatcagactc aatttaacgg tgttaaagtc ctgtctcagg acaaccagat gaaaatccag 540gttggtgcta acgatggtga aaccattacc atcgatctgc aaaaaattga tgtgaaaagc 600cttggccttg atgggttcaa tgttaattcc ccgggaattt ccggtggtgg tggtggaatt 660ctagactcca tgggtacatt aatcaatgaa gacgctgccg cagccaagaa aagtaccgct 720aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 780ggggcaattc aaaaccgttt tgattcagcc attaccaacc ttggcaatac ggtaaccaat 840ctgaactccg cgcgtagccg tatcgaagat gctgactatg caacggaagt ttctaatatg 900tctaaagcgc agattctgca gcaggctggt acttccgttc tggcgcaggc taaccaggtt 960ccgcaaaacg tcctctcttt actgcgttaa gtcgac 996143903DNAArtificial SequenceSynthetic sequence 143atgcggggtt ctcatcatca tcatcatcat ggtatggcta gcatgactgg tggacagcaa 60atgggtcggg atctgtacga cctggttccg cgcggtagcg cgaaggatcc gtctggtctg 120cgtatcaaca gcgcgaaaga cgatgcggca ggccaggcga ttgctaaccg cttcacttct 180aatatcaaag gtctgactca ggcttcccgt aacgctaacg acggcatttc tattgcgcag 240accactgaag gtgcgctgaa tgaaatcaac aacaacctgc agcgtgtgcg tgagttgtct 300gttcaggcca ctaacgggac taactctgat tccgatctga aatctatcca ggatgaaatt 360cagcaacgtc tggaagaaat cgatcgcgtt tctaatcaga ctcaatttaa cggtgttaaa 420gtcctgtctc aggacaacca gatgaaaatc caggttggtg ctaacgatgg tgaaaccatt 480accatcgatc tgcaaaaaat tgatgtgaaa agccttggcc ttgatgggtt caatgttaat 540tccccgggaa tttccggtgg tggtggtgga attctagact ccatgggtac attaatcaat 600gaagacgctg ccgcagccaa gaaaagtacc gctaacccac tggcttcaat tgattctgca 660ttgtcaaaag tggacgcagt tcgttcttct ctgggggcaa ttcaaaaccg ttttgattca 720gccattacca accttggcaa tacggtaacc aatctgaact ccgcgcgtag ccgtatcgaa 780gatgctgact atgcaacgga agtttctaat atgtctaaag cgcagattct gcagcaggct 840ggtacttccg ttctggcgca ggctaaccag gttccgcaaa acgtcctctc tttactgcgt 900taa 903144300PRTArtificial SequenceSynthetic sequence 144Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr 1 5 10 15 Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30 Ser Ala Lys Asp Pro Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp 35 40 45 Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly 50 55 60 Leu Thr Gln Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln 65 70 75 80 Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val 85 90 95 Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp 100 105 110 Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp 115 120 125 Arg Val Ser Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln 130 135 140 Asp Asn Gln Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile 145 150 155 160 Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly 165 170 175 Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu 180 185 190 Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys 195 200 205 Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val 210 215 220 Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser 225 230 235 240 Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg 245 250 255 Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser 260 265 270 Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala 275 280 285 Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Arg 290 295 300 14544DNAArtificial SequenceSynthetic sequence 145agatctccgc ggaaccagtg catagtcagc atcttcgata cggc 44146747DNAArtificial SequenceSynthetic sequence 146taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcac tggttccgcg gggttctcat 720catcatcatc atcatggtta agtcgac 747147654DNAArtificial SequenceSynthetic sequence 147atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg cactggttcc gcggggttct catcatcatc atcatcatgg ttaa 654148217PRTArtificial SequenceSynthetic sequence 148Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Leu Val Pro Arg 195 200 205 Gly Ser His His His His His His Gly 210 215 149753DNAArtificial SequenceSynthetic sequence 149atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctgc agacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactgccggg gctaacgctg atgccgctct gaaagctatc 240caggctgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctcagca gactcaagct 300gccgctgtta aagtcctgtc tcaggacaac gcaatggcaa tccaggttgg tgctaacgat 360ggtgccgcta ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggaagt ttctcaaatg tctaaagcgc agattctgca gcaggctggt 660acttccgttc tggcgcaggc taaccaggtt ccgcaaaacg tcctctcttt actggttccg 720cggggttctc atcatcatca tcatcatggt taa 753150250PRTArtificial SequenceSynthetic sequence 150Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Ala Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Ala Gly Ala Asn Ala Asp Ala Ala Leu Lys Ala Ile 65 70 75 80 Gln Ala Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Gln 85 90 95 Gln Thr Gln Ala Ala Ala Val Lys Val Leu Ser Gln Asp Asn Ala Met 100 105 110 Ala Ile Gln Val Gly Ala Asn Asp Gly Ala Ala Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Gln Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 151846DNAArtificial SequenceSynthetic sequence 151taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctgcaga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac tgccggggct 300aacgctgatg ccgctctgaa agctatccag gctgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctcagcagac tcaagctgcc gctgttaaag tcctgtctca ggacaacgca 420atggcaatcc aggttggtgc taacgatggt gccgctatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc tcaaatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846152795DNAArtificial SequenceSynthetic sequence 152taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctgcaga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac tgccggggct 300aacgctgatg ccgctctgaa agctatccag gctgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctcagcagac tcaagctgcc gctgttaaag tcctgtctca ggacaacgca 420atggcaatcc aggttggtgc taacgatggt gccgctatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc tcaaatgtct 720aaagcgcaga ttctgcagca ggctggtctg gttccgcggg gttctcatca tcatcatcat 780catggttaag tcgac 795153702DNAArtificial SequenceSynthetic sequence 153atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctgc agacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactgccggg gctaacgctg atgccgctct gaaagctatc 240caggctgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctcagca gactcaagct 300gccgctgtta aagtcctgtc tcaggacaac gcaatggcaa tccaggttgg tgctaacgat 360ggtgccgcta ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggaagt ttctcaaatg tctaaagcgc agattctgca gcaggctggt 660ctggttccgc ggggttctca tcatcatcat catcatggtt aa

702154233PRTArtificial SequenceSynthetic sequence 154Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Ala Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Ala Gly Ala Asn Ala Asp Ala Ala Leu Lys Ala Ile 65 70 75 80 Gln Ala Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Gln 85 90 95 Gln Thr Gln Ala Ala Ala Val Lys Val Leu Ser Gln Asp Asn Ala Met 100 105 110 Ala Ile Gln Val Gly Ala Asn Asp Gly Ala Ala Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Gln Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Leu Val Pro Arg 210 215 220 Gly Ser His His His His His His Gly 225 230 155990DNAArtificial SequenceSynthetic sequence 155atgcggggtt ctcatcatca tcatcatcat ggtatggcta gcatgactgg tggacagcaa 60atgggtcggg atctgtacga cgatgacgat aaggatccga tggcacaagt cattaataca 120aacagcctgt cgctgttgac ccagaataac ctgcagaaat ctcagtcctc actgagttcc 180gctattgagc gtctgtcctc tggtctgcgt atcaacagcg cgaaagacga tgcggcaggc 240caggcgattg ctaaccgctt cacttctaat atcaaaggtc tgactcaggc ttcccgtaac 300gctaacgacg gcatttctat tgcgcagacc actgaaggtg cgctgaatga aatcaacaac 360aacctgcagc gtgtgcgtga gttgtctgtt caggccactc aagggactaa ctctgattcc 420gatctgaaat ctatccagga tgaaattcag caacgtctgg aagaaatcga tcgcgtttct 480cagcagactc aatttaacgg tgttaaagtc ctgtctcagg acaaccagat gaaaatccag 540gttggtgcta acgatggtga aaccattacc atcgatctgc aaaaaattga tgtgaaaagc 600cttggccttg atgggttcaa tgttaattcc ccgggaattt ccggtggtgg tggtggaatt 660ctagactcca tgggtacatt aatcaatgaa gacgctgccg cagccaagaa aagtaccgct 720aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 780ggggcaattc aaaaccgttt tgattcagcc attaccaacc ttggcaatac ggtaaccaat 840ctgaactccg cgcgtagccg tatcgaagat gctgactatg caacggaagt ttctcaaatg 900tctaaagcgc agattctgca gcaggctggt acttccgttc tggcgcaggc taaccaggtt 960ccgcaaaacg tcctctcttt actgcgttaa 990156180DNAArtificial SequenceSynthetic sequence 156aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 60ggggcaattc aaaaccgttt tgattcagcc attaccgccc ttggcgctac ggtaaccgct 120ctggcctccg cgcgtagcgc tatcgaagat gctgactatg caacggaagt ttctcaaatg 18015760PRTArtificial SequenceSynthetic sequence 157Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val 1 5 10 15 Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg Phe Asp Ser Ala Ile Thr 20 25 30 Ala Leu Gly Ala Thr Val Thr Ala Leu Ala Ser Ala Arg Ser Ala Ile 35 40 45 Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met 50 55 60 15850DNAArtificial SequenceSynthetic sequence 158gcagttcgtt cttctctggg ggcaattgat tcagccatta ccgcccttgg 5015950DNAArtificial SequenceSynthetic sequence 159ccaagggcgg taatggctga atcaattgcc cccagagaag aacgaactgc 501601066DNAArtificial SequenceSynthetic sequence 160taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaaataattt 60tgtttaactt taagaaggag atatacatat gcggggttct catcatcatc atcatcatgg 120tatggctagc atgactggtg gacagcaaat gggtcgggat ctgtacgacg atgacgataa 180ggatccgatg gcacaagtca ttaatacaaa cagcctgtcg ctgttgaccc agaataacct 240gaacaaatct cagtcctcac tgagttccgc tattgagcgt ctgtcctctg gtctgcgtat 300caacagcgcg aaagacgatg cggcaggcca ggcgattgct aaccgcttca cttctaatat 360caaaggtctg actcaggctt cccgtaacgc taacgacggc atttctattg cgcagaccac 420tgaaggtgcg ctgaatgaaa tcaacaacaa cctgcagcgt gtgcgtgagt tgtctgttca 480ggccactaac gggactaact ctgattccga tctgaaatct atccaggatg aaattcagca 540acgtctggaa gaaatcgatc gcgtttctaa tcagactcaa tttaacggtg ttaaagtcct 600gtctcaggac aaccagatga aaatccaggt tggtgctaac gatggtgaaa ccattaccat 660cgatctgcaa aaaattgatg tgaaaagcct tggccttgat gggttcaatg ttaattcccc 720gggaatttcc ggtggtggtg gtggaattct agactccatg ggtacattaa tcaatgaaga 780cgctgccgca gccaagaaaa gtaccgctaa cccactggct tcaattgatt ctgcattgtc 840aaaagtggac gcagttcgtt cttctctggg ggcaattgat tcagccatta ccgcccttgg 900cgctacggta accgctctgg cctccgcggc tagccgtatc gaagatgctg actatgcaac 960ggaagtttct aatatgtcta aagcgcagat tctgcagcag gctggtactt ccgttctggc 1020gcaggctaac caggttccgc aaaacgtcct ctctttactg cgttaa 1066161325PRTArtificial SequenceSynthetic sequence 161Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr 1 5 10 15 Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Asp Asp Asp Lys Asp 20 25 30 Pro Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln 35 40 45 Asn Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg 50 55 60 Leu Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly 65 70 75 80 Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln 85 90 95 Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu 100 105 110 Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu 115 120 125 Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser 130 135 140 Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser 145 150 155 160 Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln 165 170 175 Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp 180 185 190 Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val 195 200 205 Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met 210 215 220 Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala 225 230 235 240 Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val 245 250 255 Arg Ser Ser Leu Gly Ala Ile Asp Ser Ala Ile Thr Ala Leu Gly Ala 260 265 270 Thr Val Thr Ala Leu Ala Ser Ala Ala Ser Arg Ile Glu Asp Ala Asp 275 280 285 Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln Ile Leu Gln Gln 290 295 300 Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val Pro Gln Asn Val 305 310 315 320 Leu Ser Leu Leu Arg 325 162180DNAArtificial SequenceSynthetic sequence 162aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 60ggggcaattg caaaggcttt tgattcagcc attaccgccc ttggcgctac ggtaaccgct 120ctggcctccg cgcgtagcgc tatcgaagat gctgactatg caacggaagt ttctcaaatg 18016360PRTArtificial SequenceSynthetic sequence 163Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val 1 5 10 15 Arg Ser Ser Leu Gly Ala Ile Ala Lys Ala Phe Asp Ser Ala Ile Thr 20 25 30 Ala Leu Gly Ala Thr Val Thr Ala Leu Ala Ser Ala Arg Ser Ala Ile 35 40 45 Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met 50 55 60 16450DNAArtificial SequenceSynthetic sequence 164cgttcttctc tgggggcaat tgcaaaggct tttgattcag ccattaccgc 5016550DNAArtificial SequenceSynthetic sequence 165gcggtaatgg ctgaatcaaa agcctttgca attgccccca gagaagaacg 501661078DNAArtificial SequenceSynthetic sequence 166taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaaataattt 60tgtttaactt taagaaggag atatacatat gcggggttct catcatcatc atcatcatgg 120tatggctagc atgactggtg gacagcaaat gggtcgggat ctgtacgacg atgacgataa 180ggatccgatg gcacaagtca ttaatacaaa cagcctgtcg ctgttgaccc agaataacct 240gaacaaatct cagtcctcac tgagttccgc tattgagcgt ctgtcctctg gtctgcgtat 300caacagcgcg aaagacgatg cggcaggcca ggcgattgct aaccgcttca cttctaatat 360caaaggtctg actcaggctt cccgtaacgc taacgacggc atttctattg cgcagaccac 420tgaaggtgcg ctgaatgaaa tcaacaacaa cctgcagcgt gtgcgtgagt tgtctgttca 480ggccactaac gggactaact ctgattccga tctgaaatct atccaggatg aaattcagca 540acgtctggaa gaaatcgatc gcgtttctaa tcagactcaa tttaacggtg ttaaagtcct 600gtctcaggac aaccagatga aaatccaggt tggtgctaac gatggtgaaa ccattaccat 660cgatctgcaa aaaattgatg tgaaaagcct tggccttgat gggttcaatg ttaattcccc 720gggaatttcc ggtggtggtg gtggaattct agactccatg ggtacattaa tcaatgaaga 780cgctgccgca gccaagaaaa gtaccgctaa cccactggct tcaattgatt ctgcattgtc 840aaaagtggac gcagttcgtt cttctctggg ggcaattgca aaggcttttg attcagccat 900taccgccctt ggcgctacgg taaccgctct ggcctccgcg gctagccgta tcgaagatgc 960tgactatgca acggaagttt ctaatatgtc taaagcgcag attctgcagc aggctggtac 1020ttccgttctg gcgcaggcta accaggttcc gcaaaacgtc ctctctttac tgcgttaa 1078167329PRTArtificial SequenceSynthetic sequence 167Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr 1 5 10 15 Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Asp Asp Asp Lys Asp 20 25 30 Pro Met Ala Gln Val Ile Asn Thr Asn Ser Leu Ser Leu Leu Thr Gln 35 40 45 Asn Asn Leu Asn Lys Ser Gln Ser Ser Leu Ser Ser Ala Ile Glu Arg 50 55 60 Leu Ser Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly 65 70 75 80 Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln 85 90 95 Ala Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu 100 105 110 Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu 115 120 125 Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser 130 135 140 Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser 145 150 155 160 Asn Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln 165 170 175 Met Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp 180 185 190 Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val 195 200 205 Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu Asp Ser Met 210 215 220 Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys Ser Thr Ala 225 230 235 240 Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val Asp Ala Val 245 250 255 Arg Ser Ser Leu Gly Ala Ile Ala Lys Ala Phe Asp Ser Ala Ile Thr 260 265 270 Ala Leu Gly Ala Thr Val Thr Ala Leu Ala Ser Ala Ala Ser Arg Ile 275 280 285 Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser Lys Ala Gln 290 295 300 Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala Asn Gln Val 305 310 315 320 Pro Gln Asn Val Leu Ser Leu Leu Arg 325 168903DNAArtificial SequenceSynthetic sequence 168atgcggggtt ctcatcatca tcatcatcat ggtatggcta gcatgactgg tggacagcaa 60atgggtcggg atctgtacga cctggttccg cgcggtagcg cgaaggatcc gtctggtctg 120cgtatcaaca gcgcgaaaga cgatgcggca ggccaggcga ttgctaaccg cttcacttct 180aatatcaaag gtctgactca ggcttcccgt aacgctgcag acggcatttc tattgcgcag 240accactgaag gtgcgctgaa tgaaatcaac aacaacctgc agcgtgtgcg tgagttgtct 300gttcaggcca ctaacgggac taactctgat tccgatctga aatctatcca ggatgaaatt 360cagcaacgtc tggaagaaat cgatcgcgtt tctaatcaga ctcaagctaa cggtgttaaa 420gtcctgtctc aggacaacgc aatgaaaatc caggttggtg ctaacgatgg tgccgctatt 480accatcgatc tgcaaaaaat tgatgtgaaa agccttggcc ttgatgggtt caatgttaat 540tccccgggaa tttccggtgg tggtggtgga attctagact ccatgggtac attaatcaat 600gaagacgctg ccgcagccaa gaaaagtacc gctaacccac tggcttcaat tgattctgca 660ttgtcaaaag tggacgcagt tcgttcttct ctgggggcaa ttcaagctcg ttttgccgcg 720gccattgcta accttggcaa tacggtaacc aatctgaact ccgcgcgtag ccgtatcgaa 780gatgctgact atgcaacgga agtttctaat atgtctaaag cgcagattct gcagcaggct 840ggtacttccg ttctggcgca ggctaaccag gttccgcaaa acgtcctctc tttactgcgt 900taa 903169300PRTArtificial SequenceSynthetic sequence 169Met Arg Gly Ser His His His His His His Gly Met Ala Ser Met Thr 1 5 10 15 Gly Gly Gln Gln Met Gly Arg Asp Leu Tyr Asp Leu Val Pro Arg Gly 20 25 30 Ser Ala Lys Asp Pro Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp 35 40 45 Ala Ala Gly Gln Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly 50 55 60 Leu Thr Gln Ala Ser Arg Asn Ala Ala Asp Gly Ile Ser Ile Ala Gln 65 70 75 80 Thr Thr Glu Gly Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val 85 90 95 Arg Glu Leu Ser Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp 100 105 110 Leu Lys Ser Ile Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp 115 120 125 Arg Val Ser Asn Gln Thr Gln Ala Asn Gly Val Lys Val Leu Ser Gln 130 135 140 Asp Asn Ala Met Lys Ile Gln Val Gly Ala Asn Asp Gly Ala Ala Ile 145 150 155 160 Thr Ile Asp Leu Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly 165 170 175 Phe Asn Val Asn Ser Pro Gly Ile Ser Gly Gly Gly Gly Gly Ile Leu 180 185 190 Asp Ser Met Gly Thr Leu Ile Asn Glu Asp Ala Ala Ala Ala Lys Lys 195 200 205 Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu Ser Lys Val 210 215 220 Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Ala Arg Phe Ala Ala 225 230 235 240 Ala Ile Ala Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg 245 250 255 Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser Asn Met Ser 260 265 270 Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu Ala Gln Ala 275 280 285 Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Arg 290 295 300 170996DNAArtificial SequenceSynthetic sequence 170taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg cggggttctc atcatcatca tcatcatggt 120atggctagca tgactggtgg acagcaaatg ggtcgggatc tgtacgacct ggttccgcgc 180ggtagcgcga aggatccgtc tggtctgcgt atcaacagcg cgaaagacga tgcggcaggc 240caggcgattg ctaaccgctt cacttctaat atcaaaggtc tgactcaggc ttcccgtaac 300gctgcagacg gcatttctat tgcgcagacc actgaaggtg cgctgaatga aatcaacaac 360aacctgcagc gtgtgcgtga gttgtctgtt caggccacta acgggactaa ctctgattcc 420gatctgaaat ctatccagga tgaaattcag caacgtctgg aagaaatcga tcgcgtttct 480aatcagactc aagctaacgg tgttaaagtc ctgtctcagg acaacgcaat gaaaatccag 540gttggtgcta acgatggtgc cgctattacc atcgatctgc aaaaaattga tgtgaaaagc 600cttggccttg atgggttcaa tgttaattcc ccgggaattt ccggtggtgg tggtggaatt 660ctagactcca tgggtacatt aatcaatgaa gacgctgccg cagccaagaa aagtaccgct 720aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 780ggggcaattc aagctcgttt tgccgcggcc attgctaacc ttggcaatac ggtaaccaat 840ctgaactccg cgcgtagccg tatcgaagat gctgactatg caacggaagt ttctaatatg 900tctaaagcgc agattctgca gcaggctggt acttccgttc tggcgcaggc taaccaggtt 960ccgcaaaacg tcctctcttt actgcgttaa gtcgac 99617179DNAArtificial

SequenceSynthetic sequence 171agatctgtcg acttaaccat gatgatgatg atgatgagaa ccccgcggaa ccagtaaaga 60gaggacgttt tgcggaacc 79172846DNAArtificial SequenceSynthetic sequence 172taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaag ctcgttttgc cgcggccatt gctaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846173250PRTArtificial SequenceSynthetic sequence 173Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Ala Arg 165 170 175 Phe Ala Ala Ala Ile Ala Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 17447DNAArtificial SequenceSynthetic sequence 174agatctcata tgagcgggtt acggatcaac agcgcgaaag acgatgc 47175846DNAArtificial SequenceSynthetic sequence 175taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctgcaga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaagctaac ggtgttaaag tcctgtctca ggacaacgca 420atgaaaatcc aggttggtgc taacgatggt gccgctatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846176250PRTArtificial SequenceSynthetic sequence 176Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Ala Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Ala Asn Gly Val Lys Val Leu Ser Gln Asp Asn Ala Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Ala Ala Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 177270DNAArtificial SequenceSynthetic sequence 177aacccactgg cttcaattga ttctgcattg tcaaaagtgg acgcagttcg ttcttctctg 60ggggcaattc aaaaccgttt tgattcagcc attaccaacc ttggcaatac ggtaaccaat 120ctgaactccg cgcgtagccg tatcgaagat gctgactatg caacggaagt ttctcaaatg 180tctaaagcgc agattctgca gcaggctggt acttccgttc tggcgcaggc taaccaggtt 240ccgcaaaacg tcctctcttt actgcgttaa 27017860DNAArtificial SequenceSynthetic sequence 178attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 6017920PRTArtificial SequenceSynthetic sequence 179Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn Ser Ala Arg Ser 1 5 10 15 Arg Ile Glu Asp 20 18046DNAArtificial SequenceSynthetic sequence 180ccttggcaat acggtaaccg ctctggcctc cgcgcgtagc cgtatc 4618146DNAArtificial SequenceSynthetic sequence 181gatacggcta cgcgcggagg ccagagcggt taccgtattg ccaagg 4618260DNAArtificial SequenceSynthetic sequence 182acggtaaccg ctctggcctc cgcgcgtagc cgtatcgaag atgctgacta tgcaacggaa 6018320PRTArtificial SequenceSynthetic sequence 183Thr Val Thr Ala Leu Ala Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp 1 5 10 15 Tyr Ala Thr Glu 20 18434DNAArtificial SequenceSynthetic sequence 184gctctggcct ccgcggctag ccgtatcgaa gatg 3418534DNAArtificial SequenceSynthetic sequence 185catcttcgat acggctagcc gcggaggcca gagc 3418660DNAArtificial SequenceSynthetic sequence 186caaaaccgtt ttgattcagc cattaccaac cttggcaata cggtaaccgc tctggcctcc 6018720PRTArtificial SequenceSynthetic sequence 187Gln Asn Arg Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr 1 5 10 15 Ala Leu Ala Ser 20 18848DNAArtificial SequenceSynthetic sequence 188gttttgattc agccattacc gcccttggcg ctacggtaac cgctctgg 4818948DNAArtificial SequenceSynthetic sequence 189ccagagcggt taccgtagcg ccaagggcgg taatggctga atcaaaac 4819039DNAArtificial SequenceSynthetic sequence 190caacagcgcg aaagccgatg cgggaggcca ggcgattgc 3919139DNAArtificial SequenceSynthetic sequence 191gcaatcgcct ggcctcccgc atcggctttc gcgctgttg 39192846DNAArtificial SequenceSynthetic sequence 192taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagcc 120gatgcgggag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846193250PRTArtificial SequenceSynthetic sequence 193Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Ala Asp Ala Gly Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 19443DNAArtificial SequenceSynthetic sequence 194gtctgttcag gccactgccg gggctaactc tgattccgat ctg 4319543DNAArtificial SequenceSynthetic sequence 195cagatcggaa tcagagttag ccccggcagt ggcctgaaca gac 43196846DNAArtificial SequenceSynthetic sequence 196taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac tgccggggct 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846197250PRTArtificial SequenceSynthetic sequence 197Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Ala Gly Ala Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 19845DNAArtificial SequenceSynthetic sequence 198ctgattccga tctgaaagct atccaggctg aaattcagca acgtc 4519945DNAArtificial SequenceSynthetic sequence 199gacgttgctg aatttcagcc tggatagctt tcagatcgga atcag 45200846DNAArtificial SequenceSynthetic sequence 200taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac tgccggggct 300aactctgatt ccgatctgaa agctatccag gctgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846201753DNAArtificial SequenceSynthetic sequence 201atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactgccggg gctaactctg attccgatct gaaagctatc 240caggctgaaa ttcagcaacg tctggaagaa atcgatcgcg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggaagt ttctaatatg tctaaagcgc agattctgca gcaggctggt 660acttccgttc tggcgcaggc taaccaggtt ccgcaaaacg tcctctcttt actggttccg 720cggggttctc atcatcatca tcatcatggt taa 753202250PRTArtificial SequenceSynthetic sequence 202Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile

Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Ala Gly Ala Asn Ser Asp Ser Asp Leu Lys Ala Ile 65 70 75 80 Gln Ala Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 20345DNAArtificial SequenceSynthetic sequence 203gccactaacg ggactaacgc tgatgccgct ctgaaatcta tccag 4520445DNAArtificial SequenceSynthetic sequence 204ctggatagat ttcagagcgg catcagcgtt agtcccgtta gtggc 45205846DNAArtificial SequenceSynthetic sequence 205taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aacgctgatg ccgctctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846206250PRTArtificial SequenceSynthetic sequence 206Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ala Asp Ala Ala Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 20745DNAArtificial SequenceSynthetic sequence 207gccactgccg gggctaacgc tgatgccgct ctgaaagcta tccag 4520845DNAArtificial SequenceSynthetic sequence 208ctggatagct ttcagagcgg catcagcgtt agccccggca gtggc 45209846DNAArtificial SequenceSynthetic sequence 209taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac tgccggggct 300aacgctgatg ccgctctgaa agctatccag gctgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846210250PRTArtificial SequenceSynthetic sequence 210Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Ala Gly Ala Asn Ala Asp Ala Ala Leu Lys Ala Ile 65 70 75 80 Gln Ala Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 211846DNAArtificial SequenceSynthetic sequence 211taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa agctatccag gctgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846212250PRTArtificial SequenceSynthetic sequence 212Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ala Ile 65 70 75 80 Gln Ala Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 21345DNAArtificial SequenceSynthetic sequence 213ctatccagga tgaaattcag gcacgtctgg cagaaatcga tcgcg 4521445DNAArtificial SequenceSynthetic sequence 214cgcgatcgat ttctgccaga cgtgcctgaa tttcatcctg gatag 45215846DNAArtificial SequenceSynthetic sequence 215taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc aggcacgtct ggcagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846216250PRTArtificial SequenceSynthetic sequence 216Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Ala Arg Leu Ala Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 21759DNAArtificial SequenceSynthetic sequence 217ggaagaaatc gatgccgttt ctgctgcgac tcaatttaac ggtgttaaag tcctgtctc 5921859DNAArtificial SequenceSynthetic sequence 218gagacaggac tttaacaccg ttaaattgag tcgcagcaga aacggcatcg atttcttcc 59219846DNAArtificial SequenceSynthetic sequence 219taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatgccgttt ctgctgcgac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846220250PRTArtificial SequenceSynthetic sequence 220Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Ala Val Ser Ala 85 90 95 Ala Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala

Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 22153DNAArtificial SequenceSynthetic sequence 221cagcaacgtc tggaagaaat cgatgccgtt tctaatcaga ctcaatttaa cgg 5322253DNAArtificial SequenceSynthetic sequence 222ccgttaaatt gagtctgatt agaaacggca tcgatttctt ccagacgttg ctg 53223753DNAArtificial SequenceSynthetic sequence 223atgagcgggt tacggatcaa cagcgcgaaa gacgatgcgg caggccaggc gattgctaac 60cgcttcactt ctaatatcaa aggtctgact caggcttccc gtaacgctaa cgacggcatt 120tctattgcgc agaccactga aggtgcgctg aatgaaatca acaacaacct gcagcgtgtg 180cgtgagttgt ctgttcaggc cactaacggg actaactctg attccgatct gaaatctatc 240caggatgaaa ttcagcaacg tctggaagaa atcgatgccg tttctaatca gactcaattt 300aacggtgtta aagtcctgtc tcaggacaac cagatgaaaa tccaggttgg tgctaacgat 360ggtgaaacca ttaccatcga tctgcaaaaa attgatgtga aaagccttgg ccttgatggg 420ttcaatgtta attccccggg aagtaccgct aacccactgg cttcaattga ttctgcattg 480tcaaaagtgg acgcagttcg ttcttctctg ggggcaattc aaaaccgctt tgattcagcc 540attaccaacc ttggcaatac ggtaaccaat ctgaactccg cgcgtagccg tatcgaagat 600gctgactatg caacggaagt ttctaatatg tctaaagcgc agattctgca gcaggctggt 660acttccgttc tggcgcaggc taaccaggtt ccgcaaaacg tcctctcttt actggttccg 720cggggttctc atcatcatca tcatcatggt taa 753224846DNAArtificial SequenceSynthetic sequence 224taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatgccgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846225250PRTArtificial SequenceSynthetic sequence 225Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Ala Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 22653DNAArtificial SequenceSynthetic sequence 226cgtttctaat cagactcaat ttgccgctgt taaagtcctg tctcaggaca acc 5322753DNAArtificial SequenceSynthetic sequence 227ggttgtcctg agacaggact ttaacagcgg caaattgagt ctgattagaa acg 53228846DNAArtificial SequenceSynthetic sequence 228taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttgcc gctgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846229250PRTArtificial SequenceSynthetic sequence 229Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Ala Ala Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 23052DNAArtificial SequenceSynthetic sequence 230gttaaagtcc tgtctcagga caacgcgatg gcaatccagg ttggtgctaa cg 5223152DNAArtificial SequenceSynthetic sequence 231cgttagcacc aacctggatt gccatcgcgt tgtcctgaga caggacttta ac 52232846DNAArtificial SequenceSynthetic sequence 232taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaacgcg 420atggcaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846233250PRTArtificial SequenceSynthetic sequence 233Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Ala Met 100 105 110 Ala Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 23453DNAArtificial SequenceSynthetic sequence 234gatgaaaatc caggttggtg ctagcgctgc tgaaaccatt accatcgatc tgc 5323553DNAArtificial SequenceSynthetic sequence 235gcagatcgat ggtaatggtt tcagcagcgc tagcaccaac ctggattttc atc 53236846DNAArtificial SequenceSynthetic sequence 236taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc tagcgctgct gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gactatgcaa cggaagtttc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846237250PRTArtificial SequenceSynthetic sequence 237Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Ser Ala Ala Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Tyr Ala Thr Glu Val Ser 195 200 205 Asn Met Ser Lys Ala Gln Ile Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 23856DNAArtificial SequenceSynthetic sequence 238gccgtatcga agatgctgac gctggagcgg aagttgctaa tatgtctaaa gcgcag 5623956DNAArtificial SequenceSynthetic sequence 239ctgcgcttta gacatattag caacttccgc tccagcgtca gcatcttcga tacggc 56240846DNAArtificial SequenceSynthetic sequence 240taatacgact cactataggg gaattgtgag cggataacaa ttcccctcta gaataatttt 60gtttaacttt aagaaggaga tatacatatg agcgggttac ggatcaacag cgcgaaagac 120gatgcggcag gccaggcgat tgctaaccgc ttcacttcta atatcaaagg tctgactcag 180gcttcccgta acgctaacga cggcatttct attgcgcaga ccactgaagg tgcgctgaat 240gaaatcaaca acaacctgca gcgtgtgcgt gagttgtctg ttcaggccac taacgggact 300aactctgatt ccgatctgaa atctatccag gatgaaattc agcaacgtct ggaagaaatc 360gatcgcgttt ctaatcagac tcaatttaac ggtgttaaag tcctgtctca ggacaaccag 420atgaaaatcc aggttggtgc taacgatggt gaaaccatta ccatcgatct gcaaaaaatt 480gatgtgaaaa gccttggcct tgatgggttc aatgttaatt ccccgggaag taccgctaac 540ccactggctt caattgattc tgcattgtca aaagtggacg cagttcgttc ttctctgggg 600gcaattcaaa accgctttga ttcagccatt accaaccttg gcaatacggt aaccaatctg 660aactccgcgc gtagccgtat cgaagatgct gacgctggag cggaagttgc taatatgtct 720aaagcgcaga ttctgcagca ggctggtact tccgttctgg cgcaggctaa ccaggttccg 780caaaacgtcc tctctttact ggttccgcgg ggttctcatc atcatcatca tcatggttaa 840gtcgac 846241250PRTArtificial SequenceSynthetic sequence 241Met Ser Gly Leu Arg Ile Asn Ser Ala Lys Asp Asp Ala Ala Gly Gln 1 5 10 15 Ala Ile Ala Asn Arg Phe Thr Ser Asn Ile Lys Gly Leu Thr Gln Ala 20 25 30 Ser Arg Asn Ala Asn Asp Gly Ile Ser Ile Ala Gln Thr Thr Glu Gly 35 40 45 Ala Leu Asn Glu Ile Asn Asn Asn Leu Gln Arg Val Arg Glu Leu Ser 50 55 60 Val Gln Ala Thr Asn Gly Thr Asn Ser Asp Ser Asp Leu Lys Ser Ile 65 70 75 80 Gln Asp Glu Ile Gln Gln Arg Leu Glu Glu Ile Asp Arg Val Ser Asn 85 90 95 Gln Thr Gln Phe Asn Gly Val Lys Val Leu Ser Gln Asp Asn Gln Met 100 105 110 Lys Ile Gln Val Gly Ala Asn Asp Gly Glu Thr Ile Thr Ile Asp Leu 115 120 125 Gln Lys Ile Asp Val Lys Ser Leu Gly Leu Asp Gly Phe Asn Val Asn 130 135 140 Ser Pro Gly Ser Thr Ala Asn Pro Leu Ala Ser Ile Asp Ser Ala Leu 145 150 155 160 Ser Lys Val Asp Ala Val Arg Ser Ser Leu Gly Ala Ile Gln Asn Arg 165 170 175 Phe Asp Ser Ala Ile Thr Asn Leu Gly Asn Thr Val Thr Asn Leu Asn 180 185 190 Ser Ala Arg Ser Arg Ile Glu Asp Ala Asp Ala Gly Ala Glu Val Ala 195 200 205 Asn Met Ser Lys Ala Gln Ile

Leu Gln Gln Ala Gly Thr Ser Val Leu 210 215 220 Ala Gln Ala Asn Gln Val Pro Gln Asn Val Leu Ser Leu Leu Val Pro 225 230 235 240 Arg Gly Ser His His His His His His Gly 245 250 2423PRTArtificial SequenceSynthetic sequence 242Ser Pro Gly 1 243293PRTArtificial SequenceSynthetic sequence 243Met Gly His His His His His His Ser Gly Met Glu Glu Phe Asn Met 1 5 10 15 Arg Ile Asn Thr Asn Val Ala Ala Met Asn Thr Tyr Ser Arg Leu Thr 20 25 30 Ala Ala Asn Thr Ala Lys Ser Asn Ser Leu Ala Lys Leu Ser Ser Gly 35 40 45 Leu Arg Ile Asn Lys Ala Gly Asp Asp Ala Ala Gly Leu Ala Ile Ser 50 55 60 Glu Lys Met Lys Ser Gln Ile Gly Gly Leu Thr Gln Ala Lys Arg Asn 65 70 75 80 Ala Gln Asp Gly Ile Ser Leu Val Gln Thr Ala Glu Gly Ala Leu Asn 85 90 95 Glu Thr His Ser Ile Leu Glu Arg Met Arg Asp Leu Ala Val Gln Gly 100 105 110 Ser Asn Gly Thr Leu Thr Ser Ser Asp Arg Gly Ser Ile Asn Lys Glu 115 120 125 Leu Lys Ala Leu His Gln Glu Leu Thr Arg Ile Ser Asn Thr Thr Glu 130 135 140 Phe Asn Thr Gln Lys Leu Phe Ser Gln Thr Lys Gln Lys Ser Val Thr 145 150 155 160 Phe Thr Phe Gln Ile Gly Ala Asn Ala Gly Gln Thr Leu Ser Val Ala 165 170 175 Ile Thr Ala Met Ser Gly Glu Ala Leu Leu Val Ser Thr Asp Ala Lys 180 185 190 Phe Ser Leu Asn Ala Ala Gly Thr Asn Ala Gly Ala Met Ile Lys Ser 195 200 205 Ile Asp Ala Ala Ile Ala Lys Val Ser Asp Gln Arg Ala Asp Leu Gly 210 215 220 Ala Val Gln Asn Arg Leu Glu His Thr Ile Asn Asn Leu Thr Ala Thr 225 230 235 240 Asn Glu Asn Leu Ser Asp Ala Asn Ser Arg Ile Arg Asp Val Asp Met 245 250 255 Ala Glu Glu Met Met Thr Phe Thr Lys Ser Asn Ile Leu Ser Gln Ala 260 265 270 Ala Thr Ser Met Leu Ala Gln Ala Asn Ala Met Pro Asn Ser Val Leu 275 280 285 Asn Leu Leu Gln Gly 290 244280PRTArtificial SequenceSynthetic sequence 244Met Gly His His His His His His Ser Gly Met Arg Ile Asn His Asn 1 5 10 15 Ile Ser Ala Leu Asn Ala Trp Arg Asn Ile Asp Gln Thr Gln Tyr Ser 20 25 30 Met Ser Lys Thr Leu Glu Arg Leu Ser Ser Gly Leu Arg Ile Asn Arg 35 40 45 Ala Gly Asp Asp Ala Ala Gly Leu Ala Ile Ser Glu Lys Met Arg Gly 50 55 60 Gln Ile Lys Gly Leu Asn Met Ala Ile Lys Asn Ala Gln Asp Ala Ile 65 70 75 80 Ser Leu Ile Gln Thr Ala Glu Gly Ala Leu Thr Glu Val His Ser Ile 85 90 95 Leu Gln Arg Met Arg Glu Leu Ala Val Gln Ala Ala Ser Asp Thr Asn 100 105 110 Thr Asn Val Asp Arg Glu Gln Ile Gln Lys Glu Ile Asp Gln Leu Arg 115 120 125 Glu Glu Ile Asp Arg Ile Ala Arg Thr Thr Glu Phe Asn Thr Lys Lys 130 135 140 Leu Leu Asp Gly Lys Leu Glu Gly Phe Arg Ser Gln Val Asp Ala Lys 145 150 155 160 Val Val Thr Gly Gly Asn Ile Asn Val Gln Leu Gly Thr Val Ser Ser 165 170 175 Lys Ala Val Glu Gly Thr Tyr Val Ile Glu Val Gly Ala Ala Glu Arg 180 185 190 Ala Ile Met Val Val Asp Ala Ala Ile His Arg Val Ser Thr Ala Arg 195 200 205 Ala Ala Leu Gly Ala Ile Gln Asn Arg Leu Glu His Thr Ile Ser Asn 210 215 220 Leu Gly Val Ala Ala Glu Asn Leu Thr Ala Ala Glu Ser Arg Ile Arg 225 230 235 240 Asp Ala Asp Met Ala Lys Glu Met Met Glu Phe Thr Lys Gln Gln Ile 245 250 255 Leu Leu Gln Ser Ser Met Ala Met Leu Ala Gln Ser Asn Thr Leu Pro 260 265 270 Gln Asn Val Leu Gln Leu Met Arg 275 280 245168PRTArtificial SequenceSynthetic sequence 245Met Gly His His His His His His Ser Gly Leu Asn Met Ala Ile Lys 1 5 10 15 Asn Ala Gln Asp Ala Ile Ser Leu Ile Gln Thr Ala Glu Gly Ala Leu 20 25 30 Thr Glu Val His Ser Ile Leu Gln Arg Met Arg Glu Leu Ala Val Gln 35 40 45 Ala Ala Ser Asp Thr Asn Thr Asn Val Asp Arg Glu Gln Ile Gln Lys 50 55 60 Glu Ile Asp Gln Leu Arg Glu Glu Ile Asp Arg Ile Ala Arg Thr Thr 65 70 75 80 Glu Phe Asn Thr Lys Lys Leu Leu Asp Gly Lys Leu Glu Gly Phe Arg 85 90 95 Ser Gln Val Asp Ala Lys Val Val Thr Gly Gly Asn Ile Asn Val Gln 100 105 110 Leu Gly Thr Val Ser Ser Lys Ala Val Glu Gly Thr Tyr Val Ile Glu 115 120 125 Val Gly Ala Ala Glu Arg Ala Ile Met Val Val Asp Ala Ala Ile His 130 135 140 Arg Val Ser Thr Ala Arg Ala Ala Leu Gly Ala Ile Gln Asn Arg Leu 145 150 155 160 Glu His Thr Ile Ser Asn Leu Gly 165 246285PRTArtificial SequenceSynthetic sequence 246Met Gly His His His His His His Ser Gly Met Ser Leu Arg Ile Asn 1 5 10 15 Asn Asn Ile Glu Ala Leu Asn Ala Trp Arg Ala Leu Asn Ser Thr Ser 20 25 30 Asn Ala Leu Gln Lys Ser Met Glu Lys Leu Ser Ser Gly Leu Arg Ile 35 40 45 Asn Arg Ala Gly Asp Asp Ala Ala Gly Leu Ala Ile Ser Glu Lys Leu 50 55 60 Arg Ala Gln Ile Arg Gly Leu Asn Gln Ala Ile Arg Asn Ala Gln Asp 65 70 75 80 Gly Ile Ser Leu Ile Gln Thr Ala Glu Gly Gly Leu Ser Glu Ile Gln 85 90 95 Asn Ile Leu Gln Arg Met Arg Glu Leu Gly Val Gln Ala Ala Asn Gly 100 105 110 Thr Leu Asn Asn Gln Asp Ile Ser Ala Ile Thr Thr Glu Leu Asn Gln 115 120 125 Leu Phe Asn Glu Ile Asp Arg Ile Ala Gly Ala Thr Glu Phe Asn Thr 130 135 140 Lys Asn Leu Leu Ala Val Ser Thr Gly Leu Val Val Thr Leu Gln Val 145 150 155 160 Gly Ala Asn Ala Gly Gln Val Ile Ala Phe Thr Ile Asp Asn Ala Gly 165 170 175 Thr Ala Ser Leu Gly Leu Ser Ser Ala Asp Leu Ala Ile Asn Asp Asn 180 185 190 Ala Ser Ala Ser Ala Phe Ile Ser Lys Val Asp Ser Ala Leu Gln Lys 195 200 205 Val Ser Thr Tyr Arg Ala Asn Leu Gly Ser Ile Gln Asn Arg Leu Glu 210 215 220 His Thr Ile Ala Asn Leu Gly Ile Ala Ser Glu Asn Leu Ser Ala Ser 225 230 235 240 Glu Ser Arg Ile Arg Asp Val Asp Met Ala Ala Glu Met Met Asn Phe 245 250 255 Thr Lys Asn Gln Ile Leu Gln Gln Ala Gly Val Ala Ile Leu Ala Gln 260 265 270 Ala Asn Gln Ala Pro Gln Ala Val Leu Gln Leu Leu Arg 275 280 285 247171PRTArtificial SequenceSynthetic sequence 247Met Gly His His His His His His Ser Gly Leu Asn Gln Ala Ile Arg 1 5 10 15 Asn Ala Gln Asp Gly Ile Ser Leu Ile Gln Thr Ala Glu Gly Gly Leu 20 25 30 Ser Glu Ile Gln Asn Ile Leu Gln Arg Met Arg Glu Leu Gly Val Gln 35 40 45 Ala Ala Asn Gly Thr Leu Asn Asn Gln Asp Ile Ser Ala Ile Thr Thr 50 55 60 Glu Leu Asn Gln Leu Phe Asn Glu Ile Asp Arg Ile Ala Gly Ala Thr 65 70 75 80 Glu Phe Asn Thr Lys Asn Leu Leu Ala Val Ser Thr Gly Leu Val Val 85 90 95 Thr Leu Gln Val Gly Ala Asn Ala Gly Gln Val Ile Ala Phe Thr Ile 100 105 110 Asp Asn Ala Gly Thr Ala Ser Leu Gly Leu Ser Ser Ala Asp Leu Ala 115 120 125 Ile Asn Asp Asn Ala Ser Ala Ser Ala Phe Ile Ser Lys Val Asp Ser 130 135 140 Ala Leu Gln Lys Val Ser Thr Tyr Arg Ala Asn Leu Gly Ser Ile Gln 145 150 155 160 Asn Arg Leu Glu His Thr Ile Ala Asn Leu Gly 165 170 248146PRTArtificial SequenceSynthetic sequence 248Met Gly His His His His His His Ser Gly Leu Asn Gln Ala Ile Arg 1 5 10 15 Asn Ala Gln Asp Gly Ile Ser Leu Ile Gln Thr Ala Glu Gly Gly Leu 20 25 30 Ser Glu Ile Gln Asn Ile Leu Gln Arg Met Arg Glu Leu Gly Val Gln 35 40 45 Ala Ala Asn Gly Thr Leu Asn Asn Gln Asp Ile Ser Ala Ile Thr Thr 50 55 60 Glu Leu Asn Gln Leu Phe Asn Glu Ile Asp Arg Ile Ala Gly Ala Thr 65 70 75 80 Glu Phe Asn Thr Lys Asn Leu Leu Ala Ala Gly Thr Ala Ser Leu Gly 85 90 95 Leu Ser Ser Ala Asp Leu Ala Ile Asn Asp Asn Ala Ser Ala Ser Ala 100 105 110 Phe Ile Ser Lys Val Asp Ser Ala Leu Gln Lys Val Ser Thr Tyr Arg 115 120 125 Ala Asn Leu Gly Ser Ile Gln Asn Arg Leu Glu His Thr Ile Ala Asn 130 135 140 Leu Gly 145 249116PRTArtificial SequenceSynthetic sequence 249Met Gly His His His His His His Ser Ala Ser Ala Phe Ile Ser Lys 1 5 10 15 Val Asp Ser Ala Leu Gln Lys Val Ser Thr Tyr Arg Ala Asn Leu Gly 20 25 30 Ser Ile Gln Asn Arg Leu Glu His Thr Ile Ala Asn Leu Gly Pro Asp 35 40 45 Gly Leu Asn Gln Ala Ile Arg Asn Ala Gln Asp Gly Ile Ser Leu Ile 50 55 60 Gln Thr Ala Glu Gly Gly Leu Ser Glu Ile Gln Asn Ile Leu Gln Arg 65 70 75 80 Met Arg Glu Leu Gly Val Gln Ala Ala Asn Gly Thr Leu Asn Asn Gln 85 90 95 Asp Ile Ser Ala Ile Thr Thr Glu Leu Asn Gln Leu Phe Asn Glu Ile 100 105 110 Asp Arg Ile Ala 115 250103PRTArtificial SequenceSynthetic sequence 250Met Gly His His His His His His Ser Asn Asn Gln Asp Ile Ser Ala 1 5 10 15 Ile Thr Thr Glu Leu Asn Gln Leu Phe Asn Glu Ile Asp Arg Ile Ala 20 25 30 Gly Ala Thr Gly Ser Gly Gly Leu Ser Glu Ile Gln Asn Ile Leu Gln 35 40 45 Arg Met Arg Glu Leu Gly Val Gln Ala Ala Asn Gly Thr Leu Asn Gly 50 55 60 Gly Ser Ala Ser Ala Phe Ile Ser Lys Val Asp Ser Ala Leu Gln Lys 65 70 75 80 Val Ser Thr Tyr Arg Ala Asn Leu Gly Ser Ile Gln Asn Arg Leu Glu 85 90 95 His Thr Ile Ala Asn Leu Gly 100 251170PRTArtificial SequenceSynthetic sequence 251Met Gly His His His His His His Ser Gly Leu Ala Gln Ala Ser Arg 1 5 10 15 Asn Ala Gln Asp Ala Ile Ser Ile Ala Gln Thr Ala Glu Gly Ala Leu 20 25 30 Asp Glu Thr Gln Ser Ile Leu Gln Arg Val Arg Glu Leu Gly Val Gln 35 40 45 Gly Ala Asn Gly Thr Leu Thr Ala Asp Asp Ile Asn Ala Leu Gln Ala 50 55 60 Glu Val Asp Gln Leu Ile Ala Glu Ile Asp Arg Ile Ala Gly Ala Thr 65 70 75 80 Glu Phe Asn Thr Gln Asn Leu Leu Asp Gly Ser Phe Thr Thr Lys Ala 85 90 95 Phe Gln Val Gly Ala Asn Ser Gly Gln Asn Met Thr Leu Thr Ile Gly 100 105 110 Lys Met Asp Thr Thr Thr Leu Gly Leu Ser Ser Ala Asp Leu Ala Ile 115 120 125 Asn Asp Asn Ala Phe Ala Asn Gly Ala Ile Ser Thr Val Asp Ser Ala 130 135 140 Leu Gln Lys Val Ser Ala Glu Arg Ala Lys Leu Gly Ala Ile Gln Asn 145 150 155 160 Arg Leu Glu His Thr Ile Ala Asn Leu Gly 165 170 252170PRTArtificial SequenceSynthetic sequence 252Met Gly His His His His His His Ser Gly Leu Ala Gln Ala Ser Arg 1 5 10 15 Gln Ala Gln Asp Ala Ile Ser Ile Ala Gln Thr Ala Glu Gly Ala Leu 20 25 30 Asp Glu Thr Gln Ser Ile Leu Gln Arg Val Arg Glu Leu Gly Val Gln 35 40 45 Gly Ala Asp Gly Thr Leu Thr Ala Asp Asp Ile Asp Ala Leu Gln Ala 50 55 60 Glu Val Asp Gln Leu Ile Ala Glu Ile Asp Arg Ile Ala Gly Ala Thr 65 70 75 80 Glu Phe Ala Thr Gln Lys Leu Leu Asp Gly Ser Phe Thr Thr Lys Ala 85 90 95 Phe Gln Val Gly Ala Ala Ser Gly Gln Asp Val Thr Leu Thr Ile Gly 100 105 110 Lys Val Asp Thr Thr Thr Leu Gly Leu Ser Ser Ala Asp Leu Ala Ile 115 120 125 Asp Ser Ala Ala Phe Ala Asp Gly Ala Ile Ser Thr Val Asp Ser Ala 130 135 140 Leu Gln Lys Val Ser Ala Glu Arg Ala Lys Leu Gly Ala Ile Gln Asn 145 150 155 160 Arg Leu Glu His Thr Ile Ala Gln Leu Gly 165 170

Claims

1.-24. (canceled)

25. A method of vaccinating a subject against a substance abuse disorder, comprising administering an effective amount of a vaccine comprising: (a) an adjuvant comprising: a flagellin-based agent comprising an amino acid sequence having at least 95% identity with SEQ ID NO: 2, and an aluminum gel or salt, wherein the ratio (w/w) of flagellin-based agent to aluminum gel or salt is about 1:500 or less and (b) an antigen, the antigen being a constituent of an infectious agent selected from a live and attenuated, killed, inactivated or toxoid, infectious agent.

26. The method of claim 25, wherein the substance abuse disorder is addiction to one or more of fentanyl, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), heroin, morphine, opium, oxycodone, hydrocodone, ketamine, phencyclidine (PCP), barbiturates, benzodiazepines, flunitrazepam, .gamma.-hydroxybutyric acid (GHB), methaqualone, hashish, marijuana, lysergic acid diethylamide (LSD), mescaline, psilocybin, amphetamine, cocaine, methylphenidate, and nicotine.

27. The method of claim 26, wherein the substance abuse disorder is addiction to methamphetamine.

28. The method of claim 26, wherein the substance abuse disorder is addiction to fentanyl.

29. The method of claim 25, wherein the antigen is the antigen of any one of the following vaccines: DTP (diphtheria-tetanus-pertussis vaccine), DTaP (diphtheria-tetanus-acellular pertussis vaccine), Hib (Haemophilus influenzae type b) conjugate vaccines, Pneumococcal conjugate vaccine, Hepatitis A vaccines, Poliomyelitis vaccines, Yellow fever vaccines, Hepatitis B vaccines, combination DTaP, Tdap, Hib, Human Papillomavirus (HPV) vaccine, Anthrax vaccine, and Rabies vaccine.

30. The method of claim 25, wherein the antigen further comprises of any one of fentanyl, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), heroin, morphine, opium, oxycodone, hydrocodone, ketamine, phencyclidine (PCP), barbiturates, benzodiazepines, flunitrazepam, .gamma.-hydroxybutyric acid (GHB), methaqualone, hashish, marijuana, lysergic acid diethylamide (LSD), mescaline, psilocybin, amphetamine, cocaine, methylphenidate, and nicotine.

31. The method of claim 25, wherein the antigen is diphtheria antigen.

32. The method of claim 25, wherein the antigen is tetanus antigen.

33. The method of claim 25, wherein the flagellin-based agent comprises the amino acid sequence of SEQ ID NO: 2.

34. The method of claim 25, wherein the flagellin-based agent comprises the amino acid sequence of SEQ ID NO: 2 and the antigen comprises succinyl methamphetamine (SMA) hapten conjugated to tetanus toxoid.

35. The method of claim 25, wherein the flagellin-based agent inhibits and abrogates the ability of neutralizing anti-flagellin antibodies to neutralize the adjuvant.

36. The method of claim 25, wherein the aluminum gel or salt is selected from aluminum hydroxide, aluminum phosphate, and aluminum sulfate.

37. The method of claim 25, wherein the flagellin-based agent and/or antigen is adsorbed to the aluminum gel or salt.

38. The method of claim 25, wherein one or more of the flagellin-based agent and aluminum gel or salt are mixed to form a stable complex.

39. The method of claim 25, wherein the flagellin-based agent and aluminum gel or salt are mixed in a ratio that is substantially below a loading capacity of the aluminum salt.

40. The method of claim 38, wherein the flagellin-based agent and aluminum gel or salt are mixed in a ratio (w/w) of about 1:500, or about 1:600, or about 1:700, or about 1:800, or about 1:900, or about 1:1000, or about 1:2000, or about 1:5000, or about 1:10000.

41. The method of claim 25, wherein the vaccine further comprises an additional adjuvant selected from oil-in-water emulsion formulations, saponin adjuvants, ovalbumin, Freund's Adjuvant, cytokines, and chitosans.

42. The method of claim 25, wherein the vaccine and/or adjuvant causes immunostimulation of one or more of a T.sub.H1 and T.sub.H2-mediated immune response.

43. The method of claim 25, wherein the administering is orally or by parenteral injection.

44. The method of claim 25, wherein the administering takes place by controlled-release or sustained-release.

45. The method of claim 25, wherein the vaccine is administered once per subject or is used in a booster strategy.